Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis

It is unclear how a single oncogenic cell primes tumorigenesis. Here the authors visualised this behaviour using a zebrafish larval skin as a model and show that RasG12V oncogenic cell is eliminated through oncogene-senescence while a gain of function mutation in p53 alters this behaviour from tumour suppressive to tumour promoting. Most tumours are thought to arise through oncogenic cell generation followed by additional mutations. How a new oncogenic cell primes tumorigenesis by acquiring additional mutations remains unclear. We show that an additional TP53 mutation stimulates primary tumorigenesis by switching oncogene-induced senescence from a tumour suppressor to a driver. Zebrafish imaging reveals that a newly emerged oncogenic cell with the Ras(G12V) mutation becomes senescent and is eliminated from the epithelia, which is prevented by adding a TP53 gain-of-function mutation (TP53(R175H)) into Ras(G12V) cells. Surviving Ras(G12V)-TP53(R175H) double-mutant cells senesce and secrete senescence-associated secretory phenotype (SASP)-related inflammatory molecules that convert neighbouring normal cells into SASP factor-secreting senescent cells, generating a heterogeneous tumour-like cell mass. We identify oncogenic cell behaviours that may control the initial human tumorigenesis step. Ras and TP53 mutations and cellular senescence are frequently detected in human tumours; similar switching may occur during the initial step of human tumorigenesis.

Automated summary

The study demonstrates that oncogenic cells can be eliminated through oncogene-induced senescence, but this behavior can be altered by a p53 mutation, leading to promotion rather than suppression of tumorigenesis. The findings provide important insights into the initial step of tumor formation.