# Towards a new therapeutic approach based on selection for function in tumors: response to Dr. Mesut Tez

Frédéric Thomas, James Degregori, Andriy Marusyk, Antoine M Dujon, Beata Ujvari, Jean-Pascal Capp, Robert Gatenby, Aurora M Nedelcu

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Frédéric Thomas, James Degregori, Andriy Marusyk, Antoine M Dujon, Beata Ujvari, et al.. Towards a new therapeutic approach based on selection for function in tumors: response to Dr. Mesut Tez. Evolution, Medicine, and Public Health, 2024, 12 (1), pp.260-261. 10.1093/emph/eoae029. hal-04840647

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# Towards a new therapeutic approach based on selection for function in tumors: response to Dr. Mesut Tez

Frédéric Thomas<fnref n="1" />,*, ID, James DeGregori², Andriy Marusyk<fnref n="3" />, Antoine M. Dujon<fnref n="1" />,⁴, Beata Ujvari⁴ ID, Jean-Pascal Capp<fnref n="5" />, Robert Gatenby<fnref n="3" /> and Aurora M. Nedelcu⁶,*

Received 20 October 2024

We would like to express our gratitude to Dr. Mesut Tez for his thoughtful and positive response to our article 'A new perspective on tumor progression: Evolution via selection for function', recently published in *Evolution, Medicine, and Public Health* [1]. Dr. Tez's reflections not only align with our main arguments but also enrich the discussion by drawing parallels between our work and Sir Richard Peto's black box epidemiology, as well as Stuart Kauffman's autocatalytic models [2, 3].

We are particularly pleased that Dr. Tez recognizes the centrality of selection for function at the tumor

level, in addition to the traditional Darwinian view of tumor progression based purely on the fitness of individual cells. His framing of cancer cell populations as 'quick problem-solvers' adept at navigating hostile environments resonates strongly with the collective adaptability and functional redundancy we sought to highlight through the ecological concept of group phenotypic compositions (GPCs) [4], that we previously adapted to tumors [5].

The emphasis Dr. Tez places on the therapeutic implications of disrupting key functional traits and networks within tumor ecosystems is of great

<footnote n="1">¹CREEC/CANECEV, MIVEGEC (CREES), University of Montpellier, CNRS, IRD, Montpellier, France; ²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA;</footnote>

<footnote n="3">³Department of Tumor Microenvironment and Metastasis, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; ⁴School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Geelong, VIC 3216, Australia;</footnote>

<footnote n="5">⁵Toulouse Biotechnology Institute, University of Toulouse, INSA, CNRS, INRAE, Toulouse, France; ⁶Department of Biology, University of New Brunswick, Fredericton, New Brunswick, Canada</footnote>

<footnote>*Corresponding authors. Frédéric Thomas, CREEC/CANECEV, MIVEGEC (CREES), University of Montpellier, CNRS, IRD, Montpellier, France. Tel: +33 4 64 41 63 18; E-mail: frederic.thomas2@ird.fr; Aurora M. Nedelcu, Department of Biology, University of New Brunswick, Fredericton, New Brunswick, Canada. Tel: 001-506-458-7463; E-mail: anedelcu@unb.ca</footnote>
significance. As he points out, this framework opens the door to
novel treatment strategies aimed at targeting the adaptive mech-
anisms that bolster a tumor's capacity for resilience. By focus-
ing on the cooperative networks and redundant pathways that
enable tumors to thrive, we believe that oncology could make
significant strides in improving patient outcomes.

In light of Dr. Tez's insightful contribution, we feel further com-
pelled to explore how these cooperative dynamics within tumor
populations might be destabilized by carefully designed and timed
interventions. The idea of disrupting oncogenic GPCs to reduce
a tumor's capacity for rapid problem-solving indeed represents a
paradigm shift in cancer treatment strategies. It is an exciting ave-
nue for future research, and we wholeheartedly agree that a deeper
understanding of these non-linear, self-organizing systems could
provide new opportunities for therapeutic breakthroughs.

We greatly appreciate Dr. Tez's engagement with our work and
the stimulating ideas he has brought forward. His response not only
validates our proposed shift towards a function-based evolutionary
perspective on cancer progression, but also opens new paths for
exploration, particularly regarding therapeutic applications.

Thank you once again for the opportunity to respond to this
excellent commentary, and we look forward to the continued dis-
cussion on this important topic.

FUNDING

F.T. is supported by the CNRS, the Hoffmann Family and by the
following grant: EVOSEXCAN project (ANR-23-CE13-0007).

AUTHOR CONTRIBUTIONS

Frédéric Thomas (Conceptualization [equal], Writing—original draft [equal]), James DeGregori (Conceptualization [equal], Writing—review & editing [equal]), Andriy Marusyk (Conceptualization [equal], Writing—review & editing [equal]), Antoine M. Dujon (Conceptualization [equal], Writing—review & editing [equal]), Beata Ujvari (Conceptualization [equal], Writing—review & editing [equal]), Jean Pascal Capp (Conceptualization [equal], Writing—review & editing [equal]), Robert Gatenby (Conceptualization [equal], Writing—review & editing [equal]), and Aurora M. Nedelcu (Conceptualization [equal], Writing—review & editing [equal])

REFERENCES

1. Thomas F, DeGregori J, Marusyk A et al. A new perspective on tumor progression: evolution via selection for function. *Evol Med Public Health* 2024;12:172–77. doi: 10.1093/emph/eoae021

2. Peto J. Cancer epidemiology in the last century and the next decade. *Nature* 2001;411:390–5. doi: 10.1038/35077256

3. Kauffman SA. The origins of order: self-organization and selection in evolution. In: *Spin Glasses and Biology. World Scientific*, 1992, pp. 61–100. doi:10.1142/9789814415743_0003

4. Farine DR, Montiglio PO, Spiegel O. From individuals to groups and back: the evolutionary implications of group phenotypic composition. *Trends Ecol Evol* 2015;30:609–21. doi: 10.1016/j.tree.2015.07.005

5. Capp JP, DeGregori J, Nedelcu AM et al. Group phenotypic composition in cancer. *Elife* 2021;10:e63518. doi: 10.7554/eLife.63518