ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma.

Autor:	Benitz S; Department of Surgery, Henry Ford Health, Detroit, Michigan., Steep A; Center of Translational Data Science, University of Chicago, Chicago, Illinois., Nasser MM; Department of Surgery, Henry Ford Health, Detroit, Michigan., Preall J; Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, New York., Mahajan UM; Department of Medicine II, University Hospital, LMU Munich, Munich, Germany., McQuithey H; Department of Surgery, Henry Ford Health, Detroit, Michigan., Loveless I; Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan., Davis ET; Department of Surgery, Henry Ford Health, Detroit, Michigan., Wen HJ; Department of Surgery, Henry Ford Health, Detroit, Michigan., Long DW; Department of Surgery, Henry Ford Health, Detroit, Michigan., Metzler T; Comparative Experimental Pathology (CEP), Institute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany., Zwernik S; Department of Surgery, Henry Ford Health, Detroit, Michigan., Louw M; Department of Surgery, Henry Ford Health, Detroit, Michigan., Rempinski D; Department of Surgery, Henry Ford Health, Detroit, Michigan., Salas-Escabillas DJ; Department of Surgery, Henry Ford Health, Detroit, Michigan., Brender SM; Department of Surgery, Henry Ford Health, Detroit, Michigan., Song L; Center of Translational Data Science, University of Chicago, Chicago, Illinois., Huang L; Department of Surgery, Henry Ford Health, Detroit, Michigan., Theisen BK; Department of Pathology, Henry Ford Health, Detroit, Michigan., Zhang Z; Center of Translational Data Science, University of Chicago, Chicago, Illinois., Steele NG; Department of Surgery, Henry Ford Health, Detroit, Michigan.; Department of Pathology, Wayne State University, Detroit, Michigan.; Department of Pharmacology and Toxicology, Michigan State University, Lansing, Michigan.; Department of Oncology, Wayne State University, Detroit, Michigan., Regel I; Department of Medicine II, University Hospital, LMU Munich, Munich, Germany., Bednar F; Department of Surgery, University of Michigan, Ann Arbor, Michigan., Crawford HC; Department of Surgery, Henry Ford Health, Detroit, Michigan.; Department of Pharmacology and Toxicology, Michigan State University, Lansing, Michigan.; Department of Oncology, Wayne State University, Detroit, Michigan.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Nov 01; Vol. 14 (11), pp. 2162-2182.
DOI:	10.1158/2159-8290.CD-24-0137
Abstrakt:	Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor PDX1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in a mouse and human. We identified the receptor tyrosine kinase ROR2 as marker of a gastric metaplasia-like identity in pancreas neoplasms. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition. Significance: We discovered the receptor tyrosine kinase ROR2 as an important regulator of cellular identity in pancreatic precancerous lesions and pancreatic cancer. ROR2 drives an aggressive PDAC phenotype and confers resistance to KRAS inhibitors, suggesting that targeting ROR2 will enhance sensitivity to this new generation of targeted therapies. See related commentary by Marasco and Misale, p. 2018. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu