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

Yukinari Haraoka, Yuki Akieda, Yuri Nagai, Chihiro Mogi and Tohru Ishitani ()
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Yukinari Haraoka: Osaka University
Yuki Akieda: Osaka University
Yuri Nagai: Osaka University
Chihiro Mogi: Gunma University
Tohru Ishitani: Osaka University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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 RasG12V mutation becomes senescent and is eliminated from the epithelia, which is prevented by adding a TP53 gain-of-function mutation (TP53R175H) into RasG12V cells. Surviving RasG12V-TP53R175H 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.

Date: 2022
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DOI: 10.1038/s41467-022-29061-6

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