Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers.

Abstract:

:Although it has become increasingly clear that cancers display extensive cellular heterogeneity, the spatial growth dynamics of genetically distinct clones within developing solid tumours remain poorly understood. Here we leverage mosaic analysis with double markers (MADM) to trace subclonal populations retaining or lacking p53 within oncogenic Kras-initiated lung and pancreatic tumours. In both models, p53 constrains progression to advanced adenocarcinomas. Comparison of lineage-related p53 knockout and wild-type clones reveals a minor role of p53 in suppressing cell expansion in lung adenomas. In contrast, p53 loss promotes both the initiation and expansion of low-grade pancreatic intraepithelial neoplasia (PanINs), likely through differential expression of the p53 regulator p19ARF. Strikingly, lineage-related cells are often dispersed in lung adenomas and PanINs, contrasting with more contiguous growth of advanced subclones. Together, these results support cancer type-specific suppressive roles of p53 in early tumour progression and offer insights into clonal growth patterns during tumour development.

journal_name

Nat Commun

journal_title

Nature communications

authors

Muzumdar MD,Dorans KJ,Chung KM,Robbins R,Tammela T,Gocheva V,Li CM,Jacks T

doi

10.1038/ncomms12685

subject

Has Abstract

pub_date

2016-09-02 00:00:00

pages

12685

issn

2041-1723

pii

ncomms12685

journal_volume

7

pub_type

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