PUBLICATION
Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis
- Authors
- Haraoka, Y., Akieda, Y., Nagai, Y., Mogi, C., Ishitani, T.
- ID
- ZDB-PUB-220320-7
- Date
- 2022
- Source
- Nature communications 13: 1417 (Journal)
- Registered Authors
- Akieda, Yuki, Haraoka, Yukinari, Ishitani, Tohru, Mogi, Chihiro
- Keywords
- none
- MeSH Terms
-
- Animals
- Carcinogenesis/genetics
- Cellular Senescence*/genetics
- Mutation
- Oncogenes/genetics
- Tumor Suppressor Protein p53/genetics*
- Zebrafish*/genetics
- PubMed
- 35304872 Full text @ Nat. Commun.
Citation
Haraoka, Y., Akieda, Y., Nagai, Y., Mogi, C., Ishitani, T. (2022) Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis. Nature communications. 13:1417.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping