Loss of p53 tumor suppression function drives invasion and genomic instability in models of murine pancreatic cancer

Tonelli, Claudia, Deschênes, Astrid, Yao, Melissa, Park, Youngkyu, Tuveson, David (January 2022) Loss of p53 tumor suppression function drives invasion and genomic instability in models of murine pancreatic cancer. BioRxiv. (Unpublished)

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Abstract

Pancreatic ductal adenocarcinoma (PDA) is a deadly disease with few treatment options. There is an urgent need to better understand the molecular mechanisms that drive disease progression, with the ultimate aim of identifying early detection markers and clinically actionable targets. To investigate the transcriptional and morphological changes associated with pancreatic cancer progression, we analyzed the KrasLSLG12D/+; Trp53LSLR172H/+; Pdx1-Cre (KPC) mouse model. We have identified an intermediate cellular event during pancreatic carcinogenesis in the KPC mouse model of PDA that is represented by a subpopulation of tumor cells that express KrasG12D, p53R172H and one allele of wild-type Trp53. In vivo, these cells represent a histological spectrum of pancreatic intraepithelial neoplasia (PanIN) and acinar-to-ductal metaplasia (ADM) and rarely proliferate. Following loss of wild-type p53, these precursor lesions undergo malignant de-differentiation and acquire invasive features. We have established matched organoid cultures of pre-invasive and invasive cells from murine PDA. Expression profiling of the organoids led to the identification of markers of the pre-invasive cancer cells in vivo and mechanisms of disease aggressiveness.

Item Type:	Paper
Subjects:	organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53 diseases & disorders > cancer > cancer types > pancreatic cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor
CSHL Authors:	Tonelli, Claudia Yao, Melissa Park, Youngkyu Tuveson, David A. Deschenes, Astrid
Communities:	CSHL labs > Tuveson lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	1 January 2022
Date Deposited:	07 Apr 2022 14:40
Last Modified:	07 Apr 2022 14:40
URI:	https://repository.cshl.edu/id/eprint/40574

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