p73 activates transcriptional signatures of basal lineage identity and ciliogenesis in pancreatic ductal adenocarcinoma

Hur, Stella K, Somerville, Tim DD, Wu, Xiaoli S, Maia-Silva, Diogo, Demerdash, Osama E, Tuveson, David A, Notta, Faiyaz, Vakoc, Christopher R (April 2023) p73 activates transcriptional signatures of basal lineage identity and ciliogenesis in pancreatic ductal adenocarcinoma. bioRxiv. (Submitted)

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Abstract

During the progression of pancreatic ductal adenocarcinoma (PDAC), tumor cells are known to acquire transcriptional and morphological properties of the basal (also known as squamous) epithelial lineage, which leads to more aggressive disease characteristics. Here, we show that a subset of basal-like PDAC tumors aberrantly express p73 (TA isoform), which is a known transcriptional activator of basal lineage identity, ciliogenesis, and tumor suppression in normal tissue development. Using gain- and loss- of function experiments, we show that p73 is necessary and sufficient to activate genes related to basal identity (e.g. KRT5), ciliogenesis (e.g. FOXJ1), and p53-like tumor suppression (e.g. CDKN1A) in human PDAC models. Owing to the paradoxical combination of oncogenic and tumor suppressive outputs of this transcription factor, we propose that PDAC cells express a low level of p73 that is optimal for promoting lineage plasticity without severe impairment of cell proliferation. Collectively, our study reinforces how PDAC cells exploit master regulators of the basal epithelial lineage during disease progression.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:	Hur, Stella K. Somerville, Timothy Wu, Xiaoli Maia-Silva, Diogo Tuveson, David A. Vakoc, Christopher R. Demerdash, Osama E.
Communities:	CSHL labs > Tuveson lab CSHL labs > Vakoc lab School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	21 April 2023
Date Deposited:	23 Oct 2023 18:45
Last Modified:	29 Feb 2024 18:42
PMCID:	PMC10153254
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41278

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