# The animal body plan revisited in light of the failure of local tissue cohesion in cancer

Jean Clairambault, Lia Sela

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Jean Clairambault, Lia Sela. The animal body plan revisited in light of the failure of local tissue cohesion in cancer. 2025. hal-05377664

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# The animal body plan revisited in light of the failure of local tissue cohesion in cancer

Jean Clairambault¹,²* and Lia Sela¹,²,³,⁴

¹Laboratoire Jacques-Louis Lions, Sorbonne Université,
4 place Jussieu, Paris, 75005, France.

²Équipe Musclées, Inria, 48 rue Barrault, Paris, 75013, France.

³Équipe CAGE, Inria, 48 rue Barrault, Paris, 75013, France.

⁴Équipe Biologie et Thérapeutique des Cancers, CRSA, Hôpital Saint-Antoine, 184 Faubourg Saint-Antoine, Paris, 75012, France.

*Corresponding author(s). E-mail(s): jean.clairambault@inria.fr;
Contributing authors: lia.sela@sorbonne-universite.fr ;

## Abstract

The body plan of multicellular animals is here revisited as the program of con-
struction, contained in the zygote as a self-extracting archive - and later borne in
all nucleated cells of any given multicellular animal - which is launched at fecun-
dation. It unfolds in embryogenesis by a succession of differentiation branchings
in the cellular matter produced by successive cell proliferations, leading to the
different cell types a multicellular organism - in its achieved form - is made of,
20 for sponges (Porifera), 200 to 400 for Humans. The body plan, once has been
physically achieved as coherent and viable the animal multicellular organism for
which it is designed, must be maintained in the different constituting tissues
and organs of the organism by local cohesion control mechanisms, some of which
might be linked to the permanent action of tissue resident macrophages, already
present from early embryogenesis. Cancer is a disease of animal multicellular
organisms only, and its beginning always occurs in a given tissue, in which some
such cohesion controls fail, firstly on differentiation, secondly on proliferation.
This essay* theoretically investigates possible control mechanisms of tissue cohe-
sion maintenance failed in cancer, attempting in particular at eliciting a role for
resident macrophages in such local tissue maintenance.

**Keywords:** Cancer, Multicellularity, Animal body plan, Evolution, Phenotype divergence, Cell types, Cell differentiation control, Tissue resident macrophages

<footnote>*Some of the theoretical arguments developed here were partly presented in a special issue, dedicated to Disorganisation, #66, 2024, of the Revue Française de Psychosomatique as “Le cancer comme désorganisation localisée du plan corporel”, pp. 83–98 (in French with English abstract, by the first author, see author’s preprint at https://inria.hal.science/hal-04837273), which has been a germ and starting point for the present essay.</footnote>
# Introduction: facts of observation and propositions on multicellularity and cancer, a breviary

1. Multicellularity is a mandatory framework to consider when trying to understand, explain and fight cancer, which is a disease of multicellular animals only.

2. Multicellularity is a daring construction that needs permanent strict control of cohesion of its cell constituents.

3. Plasticity, i.e., the capacity for a cell to rapidly change its phenotype under changing conditions in its microenvironment, is a mandatory cellular trait in such construction (in particular, in embryogenesis), which cannot be kept in cells of an achieved multicellular organism (with a few exceptions: repair, wound healing), lest the cohesion of the organism be in permanent danger of dissolving. Acquired cellular plasticity is central in cancer, and it is due to such loss of cohesion control.

4. Cancer is a disease that starts in one single tissue or organ.

5. Cancer is primarily loss of local tissue control on cell differentiation and, secondarily, on cell proliferation.

6. Physiological cell differentiation in animals makes sense within cell lineages, stemming from the zygote, with the purpose a) to develop locally cell specialisations to ensure global functions at the organism level; b) to develop compatibility and cooperativity between specialised cells (division of labour). It is absolutely opposed to plasticity, that is physiologically more and more lost in successive differentiations.

7. Loss of control on cell differentiations in cancer is histologically evidenced in plastic de-differentiations (cells swimming upstream a lineage towards a stem cell-like status) and transdifferentiations (such as the very plastic EMT/MET), which in plastic cancer cells may be responses to cellular stress induced by pathological modifications of the environmental tissue.

8. Physiological control on cell differentiation and proliferation must be ensured by a coherent ensemble of intercellular gene regulatory networks (GRNs, that may be seen as taking care of cohesion, compatibilities and cooperations between cells and between organs), an ensemble that we call the *cohesion watch*, for which we will investigate a role for macrophages at the cellular level.

9. The body plan (Bauplan) is the completely deterministic program that is carried out in physiological development by the making of cohesive cellular matter which is achieved in a stable (w.r.t. environmental pressure) multicellular animal. It is unique to a given species and it is the basic evolutionary unit in the Darwinian evolution of species.

10. The cohesion watch mentioned above is an essential part of the body plan, the unfolding of which results in the making of cohesive multicellular organisms, in their development and maintenance. In cancer, the cohesion watch is impaired, initially locally, in anatomy and in physiology, and *maintenance of tissue cohesion* fails.
# 1 The body plan: developmental program and basic unit of animal evolution

## 1.1 At the heart of the body plan: control

We sketch a hypothetical representation of the concept of animal body plan and of its evolution from a point of view which may diverge from more usual acceptances of the term body plan or *Bauplan* in evolutionary biology and of its history, which goes back to Buffon, Cuvier, Geoffroy Saint-Hilaire, von Baer, Haeckel and others (Willmore 2012) (see also (Thom 1988), ch. 5). The present essay actually proposes a point of view of research in mathematical and theoretical biology, attempting at designing a unifying vision linking multicellularity, evolution, epigenetics, development and cancer, and relying on facts of observation in biology and pathology.

The main idea underlying these arguments is *control*, a modern concept that is intrinsically linked with the Industrial Revolution of the XVIII-XIXth centuries, when engineers had to design reliable, i.e., dynamically stable, machines (think of James Watt's flyball governor of 1769 to regulate the rotation speed of a steam machine). It infused later in physiology with Claude Bernard's notion of (organism and tissue) regulation (Bernard 1865), towards homeostasis (Cannon 1932), i.e., maintenance of the conditions of life in the internal body of an animal individual. It lies presently at the grounds of control systems leading to the mathematical control theory. Far from its initial meaning of plain verification ("counter-roll", in mediaeval French contre-rolle), or later "dependence upon an external agent", or even later in experimental biology "standard of comparison" (none of these senses being used here), the term "control" has in modern times become in science a synonym of "regulation". Under the words "regulation" or less frequently "control", it has been illustrated in the works of René Thom in theoretical biology (Thom 1972, 1988, 1990). Concerning more precisely the framework of multicellularity, the concept of control has been recently studied and developed in (Bich et al. 2019; Bich 2024).

## 1.2 The body plan: a program of construction

A program, really? A plan is not just a map, it is always a program of realisation, and though elusive the notion of program in biology may be, the results of realisations of the body plan are there, species after species in the animal kingdom, and rather convincing. Yet, classical definitions of the body plan mention "a set of morphological features", but never to our knowledge the notion of program. Conversely, when René Thom questions "the notion of program in biology" (Thom 1990), nowhere can one find in his text literally the body plan... although what he calls "the regulation figure of the species" (p.143, figure being meant in the framework of an abstract geometry) is very close to it. Furthermore, we now know from experiments starting with the first mammal (the sheep Dolly 1996) cloned from a somatic cell, and more elaborate ones on Induced Pluripotent Stem Cells (IPSCs) (Takahashi and Yamanaka 2006), that potentially any nucleated cell of an animal multicellular organism should contain the complete program of making an achieved animal, stemming from the zygote.
The body plan (Bauplan) of animals, often seen as limited to its anatomical and morphological dimension, while it is as importantly concerned by the integrative con- struction of the physiology of the whole organism, is the completely deterministic program - including homeobox Hox genes for control of patterning (Mann and Glass- ford 2024) - that is carried out in physiological development by the making of cohesive cellular matter which is eventually achieved in a stable multicellular animal. It is a self-extracting archive of a developmental program, processed from the zygote until the fully constituted animal. It is unique to a given species and we propose that it is the basic evolutionary unit in the Darwinian evolution of species.

Multicellularity is indeed a mandatory framework to consider when trying to under-
stand and fight cancer, a disease of multicellular animals only (Domazet-Loso and
Tautz 2010). Multicellularity is a daring physiological construction from the zygote,
based on the body plan of each species, needing for its maintenance a strict control
of cohesion of its isogenic cell constituents, a control that is primarily lost in cancer
tissues. Furthermore, cancer is so intrinsically linked with multicellularity that spon-
taneous tumours have been found in such a rudimentary animal (5 cell types only) as
the cnidarian Hydra (Domazet-Loso et al. 2014).

The body plan may be approached from at least two different viewpoints: a
functional one, in which its essentials have been recorded in particular by W.E.G.
Müller (Müller 2001; Müller and Müller 2003) in his exploration of its fundamen-
tal constituents in *Porifera*, i.e., sponges - living fossils -, close to the hypothetical
first primitive animals, aka *Urmetazoa* (namely cell adhesion, some signal transduc-
tion, a primitive self-self and self-nonself recognition system, programmed cell death,
aka apoptosis, with identification of the corresponding molecules, conserved in evolu-
tion as akin to similar ones in more evolved animals); and another one, developed by
E.H. Davidson *et al*. in the theoretical study of developmental gene regulatory net-
works (GRNs) controlling pattern formation (Erkenbrack and Davidson 2015; Peter
and Davidson 2017; Erkenbrack *et al*. 2018).

1.3 On the origin of the body plan: recapitulation of an
evolutionary route? A scenario

Theories of recapitulation, as presented by Haeckel (Haeckel 1806) (see also (Thom
1988), pp. 118 sq.), state that “ontogeny recapitulates phylogeny”. We propose that
non stabilised, phenotypic divergences leading to branchings in the tree of life, as ini-
tial different fast responses to external (environmental) stress, as sketched in (Nedelcu
2020; Nedelcu and Michod 2020; Wagner et al. 2019), were initially sustained by
epigenetically based, reversible, mechanisms. Such branchings may be seen as differ-
ent solutions to an optimisation problem under constraints, as sketched in (Alvarez
and Clairambault 2024), citing as a possible example in paleoanthropology a diver-
gence in the early hominin lineage in South Africa due to habitat change, inducing
divergent feeding niches (Balter et al. 2012). Eventually, a genetic mutation fixed the
phenotypic divergence of the species, following a barely perturbed journey, until some
long-lasting and stochastic event - such as cellular stress due to a potentially deadly
external constraint - favoured within the species the emergence of some genetically
fixed phenotypic divergence, possibly to avoid the high energy consumption required
by epigenetic enzyme activity to ensure such divergence of phenotypes, thus defining
the genetic evolution of different species.

Such history of successive adaptations was borne as an (epigenetic) memory (Bird
2002) in each cell of any (isogenic) animal multicellular species, precisely in the pro-
gram of the body plan, as an Ariadne's thread indicating, together with positional
information (Wolpert 1969, 2011) in embryogenesis the route to be followed by the
flows of cellular matter - by extracting the proper genes from the species common
genome -, to achieve any terminally differentiated individual characteristic of the
species.

The recapitulation from phylogeny to embryogeny in a given species thus consists
of following a deterministic program - the body plan - forcing the embryonic cellular
matter, each cell bearing it and comparing it with the positional information it holds
given its hitherto development and with the neighbouring other cells, reaching by a
succession of branchings - possibly coordinated at the level of the organism - all the
tips of the developmental program which are the terminally differentiated cell types
of the organism.

In this way, within each branch of the (stochastically and genetically determined)
tree of life until its terminal tip corresponding to a given species in Darwinian evolu-
tion, a completely different (epigenetically and deterministically defined by successive
differentiations with branchings in the isogenic cellular matter) developmental tree
unfolds - a rapidly epigenetically developing tree within each rigid, genetically fixed,
branch until its tip -, following from the zygote the body plan until its complete real-
isation as a multicellular individual (see a representation sketched in (Thom 1988),
p. 169). The memory of successive phenotype divergences, genetically fixed, that
occurred, induced by successive threatening stochastic events, during the evolution of
this given species, integrated as epigenetic instructions in the program of the species
body plan, governs from the zygote its unfolding towards the realisation of each indi-
vidual of the species, constituted by the assemblage of its terminally differentiated cell
types (Zeng 2022) (classically estimated as about 200-400 in Humans).

Obviously, the closer the branches starting from a common ancestor in the tree of
evolution, the closer should be the body plans of the individuals - with close terminal
cell types, as, e.g., in mammals -, representatives of the species constituting the termi-
nal tips in the great tree of animal life. Note the difference in time scales: terminal tips
in the tree of life are genetically different species produced by Darwinian evolution in
the course of millions of years, while terminal tips in embryogenesis and development
are the different cell types, isogenic but phenotypically different, produced by devel-
opment in the making of a multicellular animal, from fecundation until birth, in the
course of weeks or months. "Recapitulation" is thus the application in embryogenesis
and development of the instructions contained in the body plan as a memory of the
successful past determining events in the evolution of the species.

1.4 The body plan in embryogenesis and development:
evo-devo

What launches the unfolding of the body plan? Nothing else than fecundation, giv-
ing rise to the zygote. Indeed, even if parthenogenesis is sometimes an option in
animal reproduction (aphids (Janzen and Boutilier 1977; Pradeu 2010), Komodo dragons (Watts et al. 2006) and others), sexual reproduction is the rule in multicellular animals if one considers it from an evolutionary point of view, as the egg is the basic propagule of the genome of a multicellular organism (Wolpert and Szathmáry 2002), ensuring its isogenic constitution, hence homogeneity in the unfolding of a plan of construction and likelihood of cohesion.

The unfolding of the body plan thus starts from the zygote and, as embryogenesis progresses, coordinating, as suggested in (Collinet and Lecuit 2021) the biophysical flow of growing cellular matter with the positional information present in each of its constituent cells. The body plan is the physiological and anatomical (or morphological) organiser of the whole organism, creating tissues - and firstly their precursors as embryological layers -, defining intermediate and terminal cell types by gradual loss of plasticity in successive differentiations. It also leaves at the organism level all necessary elements (as, for instance, biological clocks) for a coherent physiology of the newborn, and for future development, from the newborn to the adult.

How is the body plan of a given species affected by evolution? We suggest that in a non negligible part of the germinal cells of some individuals of the same species, confronted to a severe environmental stress, phenotype changes occur, adapting to it by the action of epigenetic enzymes, later being genetically fixed, and that these changes finding themselves in gametes, affect the genetic instructions of the body plan program. Then a resulting egg bearing the modified program will develop as an embryo, later an adult, with an adaptive advantage over the other representatives of its kin. Indeed, for the morphogenesis (including physiology of the organism as much as its anatomical patterning) of an individual to be changed by evolution, the organiser of development, namely the body plan, must be significantly affected by it.

# 2 Cohesion: mandatory at the organism and at the tissue levels

## 2.1 Cell lineages, cell types and phenotype divergence

In animal embryogenesis, flows of oriented cellular matter created from the first embryologic layers emerge, following in their progression the unfolding of the body plan - in which subprograms may show a realisation limited in time, as, e.g., the development of the notochord in chordates -, building by successive proliferations and differentiations the cell lineages that terminate in differentiated cell types. Such a process may be metaphorically thought of, in an inversion of the classical Waddington landscape (Waddington 1957), as analogous to the making of a wickerwork basket, stemming from a common germinal point, the zygote, each fibre - including branchings in its structure - representing one or several cell lineages. A cell type (Zeng 2022), terminal tip of such a lineage, is the prototype of a definitely differentiated cell, completely functional (from the point of view of the physiology of the organism), histologically stable and well identifiable from its physiological functions at the level of the organism, and at the individual level, from its morphological characteristics under the microscope of a pathologist.
The process at work in the making of a cell lineage in a mature tissue - the best known cases of lineages being perhaps the bone marrow cell lines (with their branchings), or the enterocyte cell line from the crypt to the villus for epithelia - or in precursor embryonic layers, relies on the activity of epigenetic agents which determine successive differentiations that involve well-controlled branchings relying on phenotype divergence. As mentioned in the previous section, such phenotype divergences should be considered as memories in the body plan of stress-induced evolutionary innovations (Wagner et al. 2019; Nedelcu 2020; Nedelcu and Michod 2020) occurred in the evolutionary course of the species. Note that, in addition to a deadly threat on the species, determining different fail-safe strategies to overcome such a challenge due to life-threatening environmental pressure, another cause of phenotype divergence (later genetically fixed in Darwinian evolution) might also come from peaceful specialisation according to different phenotypes and later cooperation between the resulting cell types to optimise the production of some common good or simply the common fitness of the species.

Both these mechanisms of phenotype divergence and cooperation have recently been modelled and schematically studied in the framework of phenotype-structured partial differential equations (PDEs) (Alvarez et al. 2022; Alvarez and Clairambault 2024). Note that the phenotype introduced in the first of these articles is multi-dimensional and may be thought of as fecundity (aka potential of proliferation), viability (aka potential to resist a deadly stress) and plasticity (aka potential to differentiate, or de-differentiate) in a population of evolving cells exposed to a gradient of divergence between the first two, supposed to be conflicting. These articles were developed to propose a PDE framework in order to mathematically represent some of the mechanisms involved in the evolution of species, as well as mechanisms of phenotype divergence, due to memories of such events, persistent in the body plan of the species and guiding differentiation according to cell lineages in the species.

## 2.2 Levels of organisation, cohesion, stability and maintenance: the cohesion watch

In the framework of multicellularity - recalling that cancer, the actual object of this essay, even though this introduction about integrative physiology may seem somehow lengthy to the reader, is a disease of animal multicellular organisms only -, two levels of between-cell organisation exist over the cell level: the tissue, or organ level, and the level of the organism itself. Clearly, at the organism level, cohesion is ensured by working cooperation and division of work between close or distant organs, like lungs, the two hearts (and their coordination of systoles and diastoles with delay between them) and the two circulatory systems, and neighbour compatibility, i.e., no trespassing of borders between close neighbouring tissues, which is normally ensured for epithelia by basal membranes except when they line dysplastic or cancerous tissues.

Conversely, the tissue or organ level is primarily concerned by cancer, as a cancer always starts locally in a tissue, and tissues are the fundamental functional bricks multicellular organisms are made of. Physiological healthiness needs existence of control at any tissue level to ensure the cohesion of the tissue from stem to mature status of
its cells, which implies control of differentiation at the tissue level. What is such con-
trol of differentiation - and by way of consequence of proliferation, as differentiation
and proliferation are usually intrinsically balanced (Bertolaso 2016; Burda and Roeder
2022; Muhr and Hagey 2021; Zhao et al. 2020) - made of? What we call the cohesion
watch (Clairambault 2020), the effects of which are clear from anatomy, in particular
through more and more investigations of homeobox genes, may be more elusive for
physiology at the organism level. Note, though, that at this general level, it may be
plainly due to functional coordination between organs by minimisation of energy con-
sumption. This may be documented by natural bioengineering representations (like a
physiologically optimised delay between the atrium and ventricle in the left and right
heart systoles) at the organism level, but at the tissue level - the level of localisation
of functions, according to Thom (Thom 1972) -, the cohesion watch, not clearly deter-
mined by bioengineering considerations, but likely relying on local tissue intercellular
gene regulatory networks (GRNs), is mandatory to regulate cell differentiation and
proliferation. Indeed, since the above mentioned fundamental bricks must be, brick
after brick, stable for the daring construction which is a multicellular organism to be
itself stable. The control of cell population, in size and number, hence in volume, in
a localised tissue or in an organ, relies on both cell proliferation control and on the
control of cell differentiation from stem until terminally differentiated state. This is
the role of the local tissue cohesion watch, for which we will explore a possibly major
contribution of tissue resident macrophages (TRMs).

Such tissue cohesion is mandatory during embryogenesis, and we suggest that the
program of the body plan, involving cellular matter flow and positional information
control, ensures this task until birth of a young animal, but it must also involve main-
tenance of tissue cohesion in adults, so that a stabilising biological entity, controlling
in particular a balance between cell differentiation and cell proliferation, should exist,
locally in each tissue. We suggest that the body plan, in the same way as it leaves
the organism stably consistent thanks to its anatomical constituents, should leave in
each tissue a cohesion agent, specific of the tissue - which may orient us towards tissue
self/nonself recognition entities -, to control cell differentiation and proliferation.

## 2.3 Plasticity and cell differentiation control in tissues

Plasticity may be understood for a cell or a tissue as rapidity to adapt to changing
environmental conditions, but it should also be thought of as the opposite of cell or
tissue differentiation, i.e., de-differentiation upstream a cell lineage or transdifferen-
tiation across cell lineages. The case of cancer (Shen and Clairambault 2020) will be
examined in Section 4, however it should be mentioned that in physiology, an adult
living animal like the tetrapod axolotl (Ambystoma mexicanum), having apparently
kept embryonic features, is able to completely regenerate a missing limb with all its
different tissues, in a succession of stages of proliferation, de-differentiation and re-
differentiation within a plastic tissue, called the blastema (McCusker et al. 2014),
stemming from a fresh wound. Such deed must be done by resorting to the epigenetic
memory (as sketched in (Bird 2002)) of the body plan program of morphogenesis,
involving strict control of successive cell differentiations and proliferations in a plastic
tissue where its instructions are still as valid as in an embryo.
In the Human species, wound healing and tissue repair have been a subject of investigation for quite a long time. Although the complete physiological process is not completely clear and should differ according to different tissues (the best known one being likely skin epithelium), a succession of phases seems to involve acquisition of de-differentiations towards stem-like cell plasticity to allow tissue remodelling, followed by re-differentiations to achieve a recovered tissue in all its terminally differentiated cells (Sarate et al. 2024). Note that differentiation of macrophages recruited from the bone marrow has also been shown to play a role in this process (Kotwal and Chien 2017).

The process of physiological tissue repair, to our meaning, thus suggests the existence of a tissue cohesion mechanism, part of the body plan program, likely linked to externally recruited macrophages from the bone marrow in case of emergency, but it also as likely suggests, when no emergency mechanism is necessary, and only the normal cohesion of the resting tissue must be ensured by a tissue-intrinsic mechanism to make each tissue a reliable brick for the construction and stability of the whole organism, the existence of a mechanism of regulation of local cell differentiations in which TRMs might be involved.

Physiological control on plasticity is thus control on the balance between differentiation and proliferation; it has been mentioned in the previous Section and studied in (Bertolaso 2016) from a relational point of view. From a molecular point of view, it should rely on the control of gatekeeper genes, themselves controlling entry in the cell division cycle in early G1 phase. How is such control of gatekeeper genes precisely related to control of differentiation has been mentioned in different studies (Burda and Roeder 2022; Muhr and Hagey 2021; Zhao et al. 2020), however the molecular bases of such balance remain to be elucidated. As regards plain tissue homeostasis by cohesion maintenance, as far as cytokines might be involved, one may expect anti-inflammatory cytokines to be more involved than pro-inflammatory ones. We agree with Marta Bertolaso (Bertolaso 2016), citing in particular (Harris 2004) about cancer, that control of differentiation - and its loss in cancer - should be prior to control on proliferation, as proliferation is commonplace in all cells, while cell differentiation is essential in multicellularity development in the framework of the construction of an evolved organism following the program of a body plan.

# 3 A role for tissue resident macrophages in local tissue cohesion control?

## 3.1 The immune system as a component of the cohesion watch

Maintaining an organism coherent and viable requires, in a constantly evolving environment, an ability to discriminate between self and non-self, with the necessary limitations such notions may involve (Pradeu 2012), leading up to the efficient elimination of foreign elements. This vital task is performed by the immune system, a structure displaying various degrees of complexity across Metazoans, suggested to be possessed even by the living fossils, Urmetazoan-like Porifera (Müller 2001; Müller and Müller 2003). On that account, the immune system serves as the principal entity
responsible for the maintenance of organismal identity, as it bears the critical role of
determining which cellular components belong to the organism and which do not. This
control operation leads to the elimination of abnormal cells, i.e., cells that deviate
from the differentiation route deterministically programmed for them. In that sense,
the immune system is a major regulator ensuring, at the cellular level, the proper
unfolding of the body plan.

Yet, following the concept of “extended immunity” (Pradeu 2012, 2020), the immune system is now recognised to carry out various other activities necessary for maintaining homeostasis within an animal multicellular organism. It has been proposed that the inflammation-related immunity represents the end of a continuum of processes that occur repeatedly throughout the life of the organism, and that are chiefly imperceptible in the absence of injury or infection (Medzhitov 2008). Of note, from early development to death, the immune system participates in maintaining cell population mass homeostasis through debris clearance, supports the development and repair of various tissues, and restores tissue integrity following inflammation. The immune system also bolsters the division of labour, when cells are partners in a cooperation framework within a tissue, by promoting long-distance cellular communication and removing non-cooperative elements (Pradeu 2020) and by controlling cellular differentiation, notably during tissue regeneration (Alshoubaki et al. 2022).

Performed by macrophage-like cells in most if not all Metazoans (Buchmann 2014), phagocytosis is seemingly one of the key mechanisms endowing the immune system with the crucial role of maintaining the physiological integrity of the organism. In the following, we will focus on TRMs, an immune population present in most tissues since early embryogenesis and markedly involved in tissue homeostasis, to explore, beyond phagocytosis, the engagement of TRMs in cohesion maintenance.

## 3.2 Macrophage central homeostatic functions promote physiological integrity

The history of macrophages begins with Metchnikoff's discovery in the late XIXth century, when he identified phagocytes, cellular agents able to move freely within the organism and to ingest particles. Interestingly, with a visionary perspective, he proposed phagocytosis to be the main mechanism involved in a harmonising process, that he called "physiological inflammation", leading to the structuration and maintenance of organismal identity (Tauber 2003). For a long time overshadowed by their role in inflammation and in pathologies, modern advances on macrophage biology - including the emergence of single cell techniques and systems biology approaches - led to a significant revision of the role of macrophages in mammalian homeostasis (Wynn et al. 2013; Davies et al. 2013; Wynn and Vannella 2016).

This is true, in particular, of the mononuclear phagocyte system (MPS) theory, according to which bone marrow-derived monocytes are the sole macrophage progenitors; in the same way, in the same theory, the assumption according to which they greatly outperform local proliferation in the maintenance of populations of TRMs has been challenged (Hume 2006). It is now admitted that in both vertebrates and invertebrates, there exist populations of TRMs developing during embryogenesis, in the yolk sac and in the fetal liver for vertebrates, that invade almost all tissues, and persist
to adulthood through local proliferations (Mass et al. 2023). Hereafter, populations
of macrophages that reside physiologically in tissues, either deriving from embryonic
precursors or from bone marrow monocytes, in unclear and tissue-specific proportions,
will be referred to as TRMs.

Despite strong phenotypical heterogeneity and organ-specificity, TRMs across tis-
sues in vertebrates display similar phenotypes (Theret et al. 2019) and exhibit core
functions all related to maintaining the integrity of the organism. Present since
embryogenesis, TRMs are major regulators of morphogenesis and development, ensur-
ing the coherent realisation of the body plan, leading up to a stable and viable
organism. TRMs support the development of their tissues of residence, primarily pre-
natally but also postnatally, during physiological homeostasis and tissue regeneration,
in particular by participating in cell fate decisions.

Perhaps most strikingly, TRMs are required for bone development; a process that
occurs prenatally but also continuously in the adult skeleton. In addition to debris
removal by phagocytosis, TRMs regulate the balance between pre-osteoclast prolifera-
tion and osteoclast differentiation, through the release of various cytokines, - including
IFN-γ, TNF-α, and IL-6 (Weivoda and Bradley 2023). The osteoclast population itself
is a specific population of TRMs involved in bone mass control as Csf1<sup>op/op</sup> mice,
i.e. mice carrying null mutations in the Csf1 gene - essential for the recruitment and
differentiation of macrophages -, exhibit osteoclast depletion and develop osteopetro-
sis (Pollard 2009), a severe disorder of bone resorption. Furthermore in-vitro studies
support a direct implication of TRMs in the control of osteoblast differentiation (Gong
et al. 2016).

Microglia, brain resident macrophages, are crucial for brain development. Prena-
tally, they participate in neurogenesis, as they regulate neural progenitors numbers
through phagocytosis, and produce diverse cytokines controlling the differentiation vs.
proliferation balance. Postnatally, microglia cells control synaptic plasticity as they
participate in synaptic pruning, phagocyte dying neurons and influence oligodendro-
genesis. For a comprehensive review of the multifarious roles of microglia in brain
development, we refer to (Hammond et al. 2018). In other internal organs, TRMs per-
form central homeostatic functions. For instance, Kupffer cells in the liver, in addition
to debris clearance, regulate iron and lipid homeostasis (Scott and Guilliams 2018)
and influence hepatic progenitor fate (Boulter et al. 2012). In the spleen, different
TRMs eliminate debris and promote the organization of the tissue (Nobs and Kopf
2021), as they can control the differentiation and proliferation of other cell types such
as dendritic cells through CSF1R-mediated signalling (Percin et al. 2018). In barrier
tissues, TRMs likewise display similar behaviours that are beginning to be explored
notably in the lung, in the skin and in the oral mucosa. One particularly well-studied
case is wound healing and tissue repair, which will be the focus of the next subsection.

3.3 Tissue cohesion disruption: macrophages in tissue repair

Ruptures of tissue cohesion can take various forms, the most striking to our view is
cancer, reviewed in Section 4; but it also happens in the context of infection from a
external organism or tissue injury; while tissue repair and regeneration are essential
components of multicellularity. In addition to their homeostatic and developmen-
tal functions exposed above on the strength of a significant phenotypic plasticity,
macrophages critically support tissue repair by guiding the resolution of inflammation
and the remodelling of the injured tissue (Mantovani et al. 2013). M1 pro inflam-
matory macrophages undergo a dynamic shift during inflammation towards a M2
pro-regenerative phenotype, supporting the restoration of functional tissue integrity.
Through the release of cytokines, debris clearance and direct interactions with other
immune and non immune cells, pro-regenerative M2 macrophages guide the tissue
towards a homeostatic condition.

Although characterising macrophages may involve many more characteristics than
M1 and M2 phenotypes, as described in detail in (Blériot et al. 2020), we are mainly
interested in control by macrophages of cell plasticity and differentiation, so that
these simple functional categories, from our point of view understood as M1-like
involved in pro-inflammation and pro-plasticity, and M2-like in pro-homeostasis and
anti-plasticity, will be our main guidelines as regards macrophage phenotypes.

These respective roles of M1-like and M2-like macrophages have been described
in particular in well-studied pathologies such as Multiple Sclerosis (MS) and Acute
Myocardial Infarction (AMI). In MS, inflammatory phases induce the impairment of
oligodendrocytes and the destruction of the myelin sheath, while its reconstruction
occurs in the recovery phases, in which M2-like macrophages are predominantly dis-
tributed in the parts concerned by MS in the Central Nervous System (Miron et al.
2013). AMI and its recovery, investigated in-vivo by experimental ischemia and reper-
fusion studies, is also known to involve macrophages in the very same roles, M2-like
primitive (of embryonic origin) TRMs being major contributors to homeostasis both
in the basic healthy state and in post-ischemia recovery, while M1-like monocyte-
recruited macrophages predominate in the ischemic phase of AMI (Peet et al. 2020;
Yang et al. 2023; Weinberger et al. 2024).

Mainly, macrophages release anti-inflammatory cytokines (IL-10, TGF-β1) that
contribute to immunomodulation; provide critical signals such as the growth factor
PDGF that promote angiogenesis (Wynn and Vannella 2016); and interact with var-
ious cell types to regulate tissue remodelling. Interestingly, macrophages influence
tissue progenitor and stem cell differentiation in various tissues, as they are notably
involved in significant crosstalk with mesenchymal stem cells (MSCs) and can affect
MSC proliferation, motility, and differentiation into adipocytes, osteoblasts, chondro-
cytes, and other cell types (Lu et al. 2021; Wang et al. 2025). Macrophages also operate
important interactions with fibroblasts, promoting their recruitment, survival and dif-
ferentiation into myofibroblasts to reinforce extracellular matrix deposition and thus
ensuring proper tissue remodelling (Wang et al. 2025).

Hence, tissue repair and regeneration involve tightly regulated interactions between
macrophages and other cellular components, from the inflammatory phase to inflam-
mation resolution and tissue remodelling. In addition to restoring the tissue structure,
TRMs and more occasionally short-lived monocyte-derived macrophages (Rodríguez-
Morales and Franklin 2023) contribute to recover the functional coherence of the tissue
during its repair. The study of macrophages outside of inflammatory contexts - during
tissue repair and homeostasis -, together with a novel exploration of their ontogeny,
sheds light on the fundamental abilities for detection, suppression and reconstruc-
tion with which macrophages are endowed. Maintenance of tissue cohesion needs to
be apprehended from a dynamical framework, and indications from above mentioned
results suggest a role for TRMs in the physiological maintenance of cohesion.

## 3.4 Macrophage polarisation and the control of differentiation/plasticity

Macrophages are very plastic cells endowed with the capacity to acquire different phenotypes depending on the local environmental signals they receive. M1 and M2 represent the two extremes of a phenotypic spectrum describing respectively a pro-inflammatory microbicidal state at one end and an anti-inflammatory pro-resolution state at the other. TRMs and their diverse homeostatic behaviours previously described align with M2-like properties (Davies et al. 2013), and embryonic TRMs harbour M2-like transcriptional programs and phenotypes (Mantovani et al. 2013) to promote the resolution of inflammation (Wynn and Vannella 2016; Wang et al. 2025). It is becoming clear that immune cells - particularly TRMs and regulatory T cells - are involved in significant physiological crosstalks with stem and progenitor cell to regulate their cellular phenotypic state, across many tissues (Naik et al. 2018). TRMs were shown to carry out tightly regulated mechanisms of stem or stem-like cell differentiation in the bone marrow, the mammary gland, the intestinal crypts, the CNS, the skin, skeletal muscles, the bone, the liver and so on (Naik et al. 2018; Alshoubaki et al. 2022).

Interestingly, several in-vitro studies indicate a differential role for M1 and M2 macrophages, reporting a pro-differentiation, i.e., anti-plasticity, role for M2 and an anti-differentiation, i.e., pro-plasticity, role for M1. This is in particular the case of brain microglia, for which the M2-like activation state promotes neural stem cell differentiation into neurons (Hammond et al. 2018) and oligodendrocytes (Miron et al. 2013), whereas M1-like microglia directly inhibits this differentiation (Hammond et al. 2018). In the bone, studies further corroborate the same specific differential role of macrophagic polarisation in mesenchymal stem cell to osteoblast differentiation (Gong et al. 2016). Anti-inflammatory factors secreted by M2-like macrophages have been shown to promote the differentiation of myogenic precursor cells into myocytes whereas pro-inflammatory factors inhibit this differentiation (Salier et al. 2013). Macrophage-derived glutamine, which is specific to M2 metabolism has been described as a mediator of muscle satellite cell proliferation and differentiation in muscle-injury mouse models (Rodríguez-Morales and Franklin 2023).

Concerning the effect of macrophages on progenitor cell proliferation, it appears
that M2-like macrophages display pro-proliferative abilities and M1-like macrophages
can inhibit proliferation, as it has been shown for mesenchymal stem cells (Lu et al.
2021).

Macrophages are involved in the development of many if not all tissues, both during
embryogenesis and in adulthood, participating in the maintenance of stability and
cohesion between cells and tissues, including in situations of tissue injury and infection.
They exhibit significant crosstalks with progenitor cells, enabling their differentiation
and proliferation to ensure the coherent development and regeneration of the tissue
they are part of. In that sense, we suggest that they constitute dynamic effectors
of the cohesion watch, able to control the proper realisation of each cellular body
plan. Future research is thus expressly needed on those aspects, noticeably because
understanding more distinctly the effect of macrophagic polarisation and ontogeny
in the physiological and pathological control of tissues is a first step to investigate
its deregulation in a cancerous context. We suggest that carcinogenesis constitutes a
continuum of states closely interconnected with abnormal immune activities, a matter
that will be explored in the following section.

# 4 Cancer as primary failure of local control on cell differentiations in tissues

## 4.1 Plasticity and uncontrolled cell differentiation in cancer

Identified as a cancer hallmark (Hanahan 2022), cellular phenotypic plasticity can
be apprehended from a theoretical perspective as a potential to quickly differentiate
or de-differentiate under the pressure of an external stimulus. It is thus opposite to
the status of a terminally differentiated cell, which must be considered to be of zero
plasticity.

Plasticity relies on the action of epigenetic enzymes (Shen and Clairambault 2020),
inducing a quick response of the cells in a tumoral tissue to cell life-threatening insults,
such as due to cytotoxic drugs. It is thus in principle reversible, as long as no genetic
change has occurred, and so must it be, since the time scale of genetic adaptation is
much too long to allow for a quick response, which is not the case of epigenetic adap-
tation. This is all the more possible as phenotypic plasticity in cancer cells is present
without the need of adaptation by genetic mutation, i.e., by enhanced availability (of
epigenetic nature) of expression of genes that are normally repressed in health, mak-
ing the tissue less rigid in its organisation, temporarily unstable as in the case of tissue
repair (see 3.3). Note also that intratumoral cooperation towards survival (Capp et al.
2023) may be interpreted as traces of the initial multicellular body plan program, as if
an already well-organised tumour tried to build itself as a new organ, producing coop-
erative survival strategies (Polyak and Marusyk 2014; Cleary et al. 2014; Tabassum
and Polyak 2015).

Later, if life-threatening events persist for a sufficiently long time, reversion of such
phenotype responses may become more difficult, as has been suggested by in-vitro
experiments on NSCLC cell populations exposed to various anticancer drugs, yielding
firstly drug tolerant persister cells (DTPs, sheer survivors without proliferative capac-
ity), and then drug tolerant expanded persisters (DTEPs, surviving and proliferating
cells) (Sharma et al. 2010), still without new mutations, since cessation of exposure
to an anticancer drug makes the newly formed viability process reversible. However,
as energy-costly epigenetic enzymes have been shown to be involved in this process,
if life-threatening insults persist in time, phenotype fixing by actual mutations may
occur, by-passing the costly activity of epigenetic enzymes, and this all the more so
(although this is not necessarily sufficient to create immediately relevant mutations)
as pre-existing mutations in cancer cells may affect the epigenetic control of gene expression, which in turn may cause new mutations (You and Jones 2012).

What is meant here by “less rigid in its organisation, temporarily unstable” is a tissue in which control of differentiations is impaired, allowing de-differentiations and transdifferentiations, as mentioned in the previous section. In fact, we contend with Marta Bertolaso (Bertolaso 2016) that what may be regarded as the main cause of cancer in a given tissue is impaired control of its cell differentiations, impairment of proliferations being associated to it, likely by way of consequence, since - as suggested by the case of stem cells - in general, dividing cells do not differentiate, and vice-versa (and differentiation, when it occurs, occurs in G0-early G1 phase, i.e., before cells can engage in the division cycle, and not as a consequence of division at mitosis) (Burda and Roeder 2022; Muhr and Hagey 2021; Zhao et al. 2020). Such unbalance between differentiation and proliferation in cancer is in particular metaphorically represented by so-called cancer attractors in the Waddington epigenetic landscape by Sui Huang et al. (Huang et al. 2009), where in the cancer case, when differentiation is blocked, as is the case in acute myelogenous leukaemias (AMLs), cells going down a differentiation valley fall into a potential well (“unused attractor”) and accumulate there by continuing proliferation. The fate of all cells, whether or not they are included in highly organised constructions, is indeed either to die, or to become two: “proliferation is the default state of all cells” (Soto and Sonnenschein 2011) as long as no mechanism external to the cell represses cell division, as for instance in the case of most neurons in an adult animal. Since, as mentioned above, proliferation is intrinsically physiologically balanced with differentiation - the molecular bases of such balance remaining to be documented -, and loss of control on differentiation is the main cause of cancer, loss of control on proliferation is a characteristic trait of all cancers, and all multicellular animals (except likely eutelic ones, such as the nematode C. elegans, since cancer implies loss of control on proliferations, that are absent in eutely), from Hydra to Humans, may be subject to cancer. This has effectively been documented in all bilaterians, and in Hydra (Domazet-Loso et al. 2014), however thus far not in Porifera.

## 4.2 Macrophages in cancer

Undoubtedly, the immune system is critically involved in cancerous conditions, both as a tumour initiation inhibitor and as a promoter of carcinogenesis. Unravelling the complex and often opposite roles of immune cells during cancerisation constitutes a major current research challenge, as the tumour micro-environment (TME) is attracting increasing attention as immunotherapies have been soaring in the past 10 years, in particular anti-PD1 drugs, and are now implemented in the clinic of cancers (Robert et al. 2015a,b).

We suggest that investigating the cancerous context-specific immune activities in light of the regulatory mechanisms involved in tissue homeostasis and in development, with a focus on tumour-associated macrophages (TAMs), usually the main immune population located in the TME (Cassetta and Pollard 2023), could lead to new therapeutic strategies. This suggestion is but a partial view of all controls that may be active in tumorigenesis, particularly if one takes into account distant influences at the organismal level of the tumour organismal environment (Laplane et al. 2019).
TAMs, generally presented as tumour-promoting M2-like macrophages with pro-proliferative, pro-angiogenic and immunosuppressive activities (Boutilier and Elsawa 2021), nevertheless exhibit extensive heterogeneity (Bied et al. 2023) and different ontogenies (Laviron and Boissonnas 2019), making the underlying mechanisms difficult to tackle. Through the recognition of dynamical and local signals, TAMs control cellular proliferation, as M1-like TAMs can directly or indirectly kill tumour cells whereas M2-like TAMs promote tumour cell proliferation by secreting various growth factors and indirectly by immunosuppression (Boutilier and Elsawa 2021; Pan et al. 2020). TAMs also engage in notable crosstalks with cancer stem cells (CSCs), as they have been shown to co-localise with CSCs and to enhance - even induce - cancer cells stemness by direct cell contact (Sharma et al. 2021) and via the release of diverse cytokines (TGF-β, IL-6/10, TNF-α) (Chen et al. 2018; Fan et al. 2014; Poggetto et al. 2021; Sica et al. 2017).

Two main types of immune de-cohesion have been associated with cancer (Pradeu 2020) : on the one hand, abnormal regulation of homeostatic immune activities has been shown to promote cancer; whereas on the other hand, cancers, as “wounds that do not heal” are commonly initiated by carcinogenic events - such as infection by pathogens or ingestion of toxic components -, for which the immune system normally responds but fails to achieve the resolution phase, notably because of interactions with (pre)cancerous cells “hijacking” the immune repair mechanisms leading to cancer-related non-resolving inflammation (Mantovani et al. 2008).

In our opinion, these two situations recapitulate opposite activation states of TRMs in precancerous tissues, in the sense that the failure of the immune system to resolve inflammation is linked to an under-activation of M2-like pro-resolution functions, whereas excessive activation of these properties - in particular because of interactions with neoplastic cells - contributes to cancer initiation and progression. This may constitute a first step to decipher the prognostic role of TAMs in carcinogenesis, as TRMs can, on that account, exert a protective role by re-engaging their homeostatic and developmental programs up to a certain threshold, beyond which their pro-proliferative and immunosuppressive potentials become deleterious for the healthy tissue.

It is also worth noting that the reuse of immune developmental abilities in cancerous contexts and the oncofetal reprogramming (Blériot et al. 2020; Lee and Ginhoux 2022) of TAMs supports our view of tumour as an emerging form of multicellularity - detailed in the following subsection - that is able to exploit cooperative mechanisms for its intrinsic development.

## 4.3 Atavistic theories of cancer

Popularised by physicists Davies, Lineweaver and Vincent in a series of evolving articles (Davies and Lineweaver 2011; Lineweaver and Davies 2020; Lineweaver et al. 2021; Vincent 2011), recently critically assessed (Daignan-Fornier and Pradeu 2024), the atavistic theories of cancer, following, without being aware of them, ideas close to others put forth much earlier (Israel 1996) - cancer as “integrated survival response to cellular stress conserved from unicellular organisms” -, propose that cancer is a reversion towards a plastic, unstable form of cell and tissue design, makes tissues lose some of the mandatory stabilising characteristics of cells efficiently integrated
in a multicellular organism and re-acquire characteristics of unicellular organisms. Numerous arguments have been found to support these theories, based on phylostratigraphic (Domazet-Loso and Tautz 2008, 2010) and paleogenomic (Trigos et al. 2018, 2024) studies. They oppose the somatic mutation theory (SMT), which explains the emergence of cancer by random mutations in driver genes, a theory already opposed by the tissue organisational field theory (TOFT) (Soto and Sonnenschein 2011; Huang et al. 2025), but do not inscribe within it.

The main idea of the atavistic theory is that cancer, whatever its origin may be, is characterised by repression of genes that are mandatory for integrated multicellularity and overexpression of genes compatible with unicellular life, in other words a regression towards unicellularity in the scale of evolution of multicellular organisms towards more and more complexity in body organisation. In its first version (2011), the theory suggested, by an analogy with computer science, that cancer is a rudimentary and unstable form of multicellularity, nevertheless useful in case of crash, to allow restarting from a minimal basis. This view is not present in the more recent versions of the theory, but the fundamental idea of regression towards characteristics of unicellular life, resulting in impaired integration in a given local tissue, starting point of the cancerous disease, or in higher regulations in the framework of the whole organism, is certainly still present. Note that other authors (Erenpreisa et al. 2022; Ye et al. 2020) nevertheless recently proposed, making use of Henry Heng's concept of a "genome chaos" (Heng and Heng 2021) self-organising atavistic program, in particular involving and explaining cancer aneuploidy, to consider the impairment of cancer differentiation control as part of a built-in program of adaptation to "unforeseen challenges", used physiologically in tissue repair, in cancer in de-differentiation and transdifferentiation - i.e., by the above mentioned cell and tissue plasticity -, thus reviving the initial idea (Israel 1996; Davies and Lineweaver 2011) of a "cancer program".

The atavistic theories of cancer are descriptive, not proposing causes of the emergence of cancer in a given tissue. However, if one combines them with the proposed causes of initiation by local impaired control on cell differentiation and proliferation (Bertolaso 2016), which are likely to originate from the tissue itself (Soto and Sonnenschein 2011; Huang et al. 2025), one is then led to search for a local tissue mechanism responsible for tissue cohesion by control of cell differentiation, what we call the local cohesion watch, in which TRMs might play an important role, as suggested in Section 3.

# 5 Future prospects

## 5.1 Mathematical and systems-biology modelling

Mathematical models of cell proliferation and cell differentiation, involving lineage branchings by phenotype divergence, have recently been sketched to account for reversible differentiation in cell lineages under environmental pressure represented by an advection term, and possible cooperation between the resulting differentiated new lineages (Alvarez et al. 2022; Alvarez and Clairambault 2024), to optimise criteria which can be global fitness of the cell population, or else production of common
goods. These are proposed elementary mechanisms that must be further documented
by biological experiments to make such modelling physiologically relevant.

Exchanges between proliferating cell populations and resident immune cells have
a long story in mathematical modelling, however, as far as we know, not with the aim
to endow immune cells with a capacity to control cell differentiation. This is a new
track in mathematical modelling, that we are presently investigating (Sela 2024).

In the morphological body plan of the general organism, the conserved Hox
genes and the GRNs controlling them have been known and studied for some time
already (Peter and Davidson 2011, 2017). A track of research could be to represent
a role for macrophages in such control in a systems biology-like perspective, as sug-
gested in (Luo et al. 2019) for the whole family of human Hox genes, by following
methods introduced in (Peter and Davidson 2011) in the exploration of the control by
GRNs of the body plan.

More abstractly, we would like to design for each animal species a differential
geometry structure of finite-dimensional variety (with dimension equal to the number
of cell types), going beyond the design of a metaphoric wickerwork basket as proposed
in Section 2, stemming from the germ of the zygote, with cell lineages as fibres until
tips equal to terminally differentiated cell types, and connections between fibres to
represent compatibility and cooperation between cell lineages.

However, one should keep in mind that, as far as our interest is in understanding
impaired local tissue cohesion in cancer, we will focus, not on anatomical morphogen-
esis of the whole animal individual, but on the genesis and maintenance of cohesion
/homeostasis) of base tissues, cell type after cell type, in an isogenic multicellular
organism in which all nucleated cells bear the potential to de-differentiate towards a
pluripotent stem cell.

## 5.2 Medical perspectives: cancer prevention and treatment

As regards prevention, one should consider a possible reversibility of precancerous
lesions. Indeed, in line with the perspective of a local tissue impaired mechanism of
control, cause of the emergence of the cancerous disease, looking for a role for TRMs in
such control, precluding somatic cell mutation as the (clear blue sky-like) only cause of
cancer, it is reasonable to consider the possibility of investigating and treating precan-
cerous lesions as diseases of tissue homeostasis - which implies investigating in detail
the action of TRMs in such tissue cohesion maintenance. It has been suggested by clin-
ical observations that in some epithelia like the oral mucosa, spontaneous reversions
of precancerous lesions have been evidenced (Villa and Woo 2017), notably with ces-
sation of tobacco consumption (Neville and Day 2002). Is it possible to make precise
a possible role for TRMs in such reversions? This could be a future track of research.

As regards treatments of established cancers, one could consider combining
antiplasticity therapies with classical antiproliferative treatments. Indeed, in the few
instances of successful redifferentiation therapies, such as ATRA (all-trans retinoic
acid) in APL (acute promyelocytic leukaemia), these therapies are associated with
cytotoxic drugs (such as anthracyclines). Instead of a not-so-easy-to-find molecular
targets such as the chimeric APL-RARα fusion gene, targeting TRMs by antiplasticity
agents acting on cancerous cells or on their dialogue with TRMs might be an option.
The extended notion of body plan that we have presented here is meant as a
theoretical biology framework to investigate the roles and phenotypes of macrophages
in maintenance - or failure of maintenance - of tissue cohesion in oral cavity epithelial
cells. When is a precancerous lesion (hyperplasia or dysplasia) in the mouth reversible
or not, what roles do macrophages play in the epithelium fate, and what therapeutics
involving them might be used to reverse a compromised fate, these are the questions at
stake that will be guiding us in the mathematical modelling of the interactions between
epithelial cell populations and macrophages, and in designing relevant bioinformatics
methods to exploit existing transcriptomic data and to propose new recordings of
biological data.

Note that the presentation of the body plan adopted here refers to the notion of closed-loop control, meant to model organism and, as far as cancer is concerned, more precisely tissue homeostasis, while open-loop control is the object of therapeutics, since representations of therapeutic interventions are meant to recover organism and tissue homeostasis, i.e., to reestablish physiological closed-loop control, with or without permanent medical corrections.

Conclusion

* The ideas developed in this essay have allowed the reader to fly over various fields of theoretical biology: evolutionary, developmental, historical, philosophical (in the sense of (Bertolaso 2016) or (Pradeu 2020)), from a point of view of mathematical modelling and control theory, presenting the body plan as a program of construction and maintenance of cohesion in multicellular animal individuals.

* Their presentation in the context of cancer (local failure of the program) and of hypotheses about the roles of tissue resident macrophages (maintenance of the result of the unfolding of the program) has to our knowledge never been broadcast to the scientific community.

* Practical implications of these ideas may lead to develop new trends in theoreti-
  cal and mathematical biology, to propose new tracks of research in the biology of
  macrophage organisation in health and in cancer, and ultimately to develop new
  methods in cancer therapeutics by intervention on tissue regulatory mechanisms by
  resident macrophages in their connections with cell populations subject to cancer.

* Limitations of these propositions are the other side of the coin of these tracks and trends. The relative lack of biological knowledge about the behaviour of macrophages in tissues hampers going further towards modelling in equations their interactions with healthy and cancer surrounding cells, and conversely, by lack of relevant mathematical and systems biology representations of these interactions, towards proposing new means of therapeutic actions in cancer tissues, involving macrophages.

* We suggest that these apparent drawbacks should in fact help foster an active field of interactive research between mathematical and experimental biology.

Acknowledgments

The authors thank the members of the LJLL and CRSA laboratories, especially
Emmanuel Trélat and Jean-Philippe Foy for valuable exchanges. L.S. is funded by PhD
scholarship “Programme Doctoral Interdisciplinaire en Cancérologie (PDIC)” of Insti-
tut Universitaire de Cancérologie (IUC) with grant contract n°5657/2024 at Sorbonne
University.

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