ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma

Benitz, Simone, Steep, Alec, Nasser, Malak M, Preall, Jonathan, Mahajan, Ujjwal Mukund, McQuithey, Holly, Loveless, Ian, Davis, Erick T, Wen, Hui-Ju, Long, Daniel W, Metzler, Thomas, Zwernik, Samuel, Louw, Michaela, Rempinski, Donald, Salas-Escabillas, Daniel J, Brender, Sydney M, Song, Linghao, Huang, Ling, Theisen, Brian K, Zhang, Zhenyu, Steele, Nina G, Regel, Ivonne, Bednar, Filip, Crawford, Howard C (July 2024) ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma. Cancer Discovery. ISSN 2159-8274 (Public Dataset)

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Abstract

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 mouse and human. We have 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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Preall, Jonathan
Communities:	CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Preall lab CSHL Cancer Center Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	8 July 2024
Date Deposited:	15 Jul 2024 13:36
Last Modified:	15 Jul 2024 13:36
Related URLs:	Publisher
Dataset ID:	GEO: GSE253600
URI:	https://repository.cshl.edu/id/eprint/41602

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