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

Autor:	Yoo HB; Department of Biochemistry, Yonsei University, Seoul, Korea., Moon JW; Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea., Kim HR; Department of Biochemistry, Yonsei University, Seoul, Korea., Lee HS; Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea., Miyabayashi K; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Park CH; Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea., Ge S; Princess Margaret Cancer Center, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Zhang A; Princess Margaret Cancer Center, Toronto, Ontario, Canada; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada., Tae YK; Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea., Sub Y; Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea., Park HW; Department of Biochemistry, Yonsei University, Seoul, Korea., Gee HY; Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea., Notta F; Princess Margaret Cancer Center, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada., Tuveson DA; Lustgarten Foundation Dedicated Laboratory at Cold Spring Harbor Laboratory, Cold Spring Harbor, New York., Bang S; Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea., Kim MY; Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea. Electronic address: miyoungkim@kaist.ac.kr., Roe JS; Department of Biochemistry, Yonsei University, Seoul, Korea. Electronic address: jroe@yonsei.ac.kr.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2023 Jul; Vol. 165 (1), pp. 133-148.e17. Date of Electronic Publication: 2023 Mar 11.
DOI:	10.1053/j.gastro.2023.02.049
Abstrakt:	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. (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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