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.
Highlights
The MIT Faculty has made this article openly available
We have previously developed autochthonous models of lung and pancreatic cancer by simultaneous Cre recombinasemediated activation of oncogenic Kras (KrasG12D) and biallelic inactivation of p53 in cells residing in the tissues of origin[11,12,13]
By comparing LSL-KrasG12D/KrasWT; p53WT/WT and LSL-KrasG12D/KrasWT; p53flox/flox mice infected with inhaled adenovirus carrying Cre recombinase, our laboratory revealed a role of p53 in limiting tumour progression from low-grade lung adenomas to advanced adenocarcinomas[11]
Summary
The MIT Faculty has made this article openly available. Please share how this access benefits you. 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. 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. We have previously developed autochthonous models of lung and pancreatic cancer by simultaneous Cre recombinasemediated activation of oncogenic Kras (KrasG12D) and biallelic inactivation of p53 in cells residing in the tissues of origin[11,12,13] These models faithfully recapitulate certain prevalent genetic alterations, histologic tumour progression, metastatic behaviour and treatment response of the human diseases. Exome-sequencing analyses of murine lung adenocarcinomas derived from LSL-KrasG12D/KrasWT; p53flox/flox mice revealed no recurrent mutations beyond Kras and p53 (ref. 16), suggesting that p53 loss is the main genetic driver of tumour progression in this model
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