Life science
Medical & healthcare, Drug development

Understanding the fundamental principles of aging andcancer for development of the preemptive medicine
Department of Homeostatic Regulation, Research Institute for Microbial Diseases
Professor Tohru Ishitani
https://researchmap.jp/read0148831

Life science

Abstract
For preventing age-related decline and extending healthy life
expectancy, preemptive medicine interfering the initial processesof aging and age-related diseases would be effective. To develop
such medical approach, the processes priming aging and age-related diseases should be clarified. Our laboratory is tackling tomake clear them using characteristic model animals and state-ofthe-art technologies. Recently, we discovered that animal tissues
possess an anti-cancer mechanism which sense and eliminate
precancerous cells in an immune cell-independent manner anddysregulation of this mechanism primes tumorigenesis, using zebrafish imaging analyses. In addition, we also succeeded in development of a platform for high-resolution screening and mechanistic
elucidation of aging regulators using an ultra-short-lived killifish
Nothobranchius furzeri (N. furzeri), which has the shortest lifespanamong laboratory animals and exhibits aging phenotypes similar to
those of humans.

▍ Significance of the research and Future perspective
Conventional aging studies using mouse models require a considerable amount of time owing to the slow pace of mouse aging.
In addition, mouse is not suitable for live imaging analysis. Therefore, these tend to focus on analyzing the factors related to known
theories of aging and cancer. By utilizing characteristic animals
including N. furzeri and zebrafish, we aim to accelerate the clarification of fundamental mechanisms controlling the initial step ofaging and cancer. Based on our discoveries, we would like to develop preemptive medicine preventing aging and cancer to extend
human health span.

▍ Background & Results
Cancer is one of the major age-related diseases. Most cancers
are thought to arise through oncogenic cell generation followed byadditional mutations. How a new oncogenic cell primes tumorigenesis by acquiring additional mutations remains unclear. To makeclear them, we developed a new experimental system for exploring
the mechanisms of primary tumorigenesis using zebrafish, a model animal suitable for live imaging (Fig 1). Our zebrafish imaging
analyses revealed that a newly emerged precancerous cell with
the RasG12V mutation becomes senescent and is eliminated fromthe epithelia, which is prevented by adding a TP53 gain-of-function
mutation (TP53R175H) into RasG12V cells. Surviving RasG12V-TP53R175H
double-mutant cells senesced and secreted inflammatory molecules that convert neighboring normal cells into either senescentor proliferative cells, generating a heterogeneous primary tumor.
Interestingly, although precancerous cells were efficiently eliminated, tissue damage including inflammation and senescenceprevented the elimination of precancerous cells and stimulated theprimary tumorigenesis. Thus, we revealed the novel mechanisms
controlling the initial step of tumorigenesis (Fig 2; Nature Commun
2019; 2022).
We are also tackling to clarify the fundamental mechanisms ofsystemic aging using an ultra-short-lived killifish N. furzeri as amodel. We successfully set up a large-scale breeding facility for N.
furzeri and establish rapid reverse genetics methods for creatingknockout and knock-in reporter N. furzeri (Sci Rep 2022). Utilizingthese methods, we have identified several new factors that control
systemic aging (in preparation).

Fig 1) Zebrafish imaging system for investigating the mechanismsunderlying primary tumorigenesis

Fig 2) Cell-Cell communication-driven mechanisms of primary tumorigenesis

Fig 3) Killifish becomes senescent within several months

P a t e n t
Haraoka, Yukinari et al. Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primarytumorigenesis. Nature Commun. 2022, 13(1), 1417. doi: 10.1038/s41467-022-29061-6
Oginuma, Masayuki et al. Rapid reverse genetics systems for Nothobranchius furzeri, a suitable model organism to study vertebrate aging. Sci Rep. 2022,
Tr e a t i s e
12(1), 11628. doi: 10.1038/s41598-022-15972-3
Akieda, Yuki et al. Cell competition corrects noisy Wnt morphogen gradients to achieve robust patterning in the zebrafish embryo. Nature Commun. 2019,10(1), 4710. doi: 10.1038/s41467-019-12609-4
https://ishitani-lab.biken.osaka-u.ac.jp/URL https://twitter.com/IshitaniLab
http://www.biken.osaka-u.ac.jp/en/achievement/research/2022/178
K e y w o r d cancer, systemic aging, preemptive medicine, mechanisms which control the initial step of aging and cancer.