RT Journal Article
SR Electronic
T1 Loss of p53 tumor suppression function drives invasion and genomic instability in models of murine pancreatic cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.31.472823
DO 10.1101/2021.12.31.472823
A1 Claudia Tonelli
A1 Astrid Deschênes
A1 Melissa A. Yao
A1 Youngkyu Park
A1 David A. Tuveson
YR 2022
UL http://biorxiv.org/content/early/2022/01/01/2021.12.31.472823.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.