A TEAD2-Driven Endothelial-Like Program Shapes Basal-Like Differentiation and Metastasis of Pancreatic Cancer

Yoo, Hye-Been, Moon, Jin Woo, Kim, Hwa-Ryeon, Lee, Hee Seung, Miyabayashi, Koji, Park, Chan Hee, Ge, Sabrina, Zhang, Amy, Tae, Yoo Keung, Sub, Yujin, Park, Hyun-Woo, Gee, Heon Yung, Notta, Faiyaz, Tuveson, David A, Bang, Seungmin, Kim, Mi-Young, Roe, Jae-Seok (July 2023) A TEAD2-Driven Endothelial-Like Program Shapes Basal-Like Differentiation and Metastasis of Pancreatic Cancer. Gastroenterology, 165 (1). 133-148.e17. ISSN 0016-5085

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Abstract

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA), with its highly metastatic propensity, is one of the most lethal subtypes of pancreatic cancer. Although recent large-scale transcriptomic studies have demonstrated that heterogeneous gene expressions play an essential role in determining molecular phenotypes of PDA, biological cues for and consequences of distinct transcriptional programs remain unclear. METHODS: We developed an experimental model that enforces the transition of PDA cells toward a basal-like subtype. We combined epigenome and transcriptome analyses with extensive in vitro and in vivo evaluations of tumorigenicity to demonstrate the validity of basal-like subtype differentiation in association with endothelial-like enhancer landscapes via TEA domain transcription factor 2 (TEAD2). Finally, we used loss-of-function experiments to investigate the importance of TEAD2 in regulating reprogrammed enhancer landscape and metastasis in basal-like PDA cells. RESULTS: Aggressive characteristics of the basal-like subtype are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of our model. Further, we showed that basal-like subtype PDA cells acquire a TEAD2-dependent proangiogenic enhancer landscape. Genetic and pharmacologic inhibitions of TEAD2 in basal-like subtype PDA cells impair their proangiogenic phenotypes in vitro and cancer progression in vivo. Last, we identify CD109 as a critical TEAD2 downstream mediator that maintains constitutively activated JAK-STAT signaling in basal-like PDA cells and tumors. CONCLUSIONS: Our findings implicate a TEAD2-CD109-JAK/STAT axis in the basal-like differentiated pancreatic cancer cells and as a potential therapeutic vulnerability.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell differentiation organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > metastasis organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor diseases & disorders > cancer > cancer types
CSHL Authors:	Tuveson, David A.
Communities:	CSHL labs > Tuveson lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	July 2023
Date Deposited:	29 Sep 2023 15:34
Last Modified:	09 Feb 2024 16:30
PMCID:	PMC10330865
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41059

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