ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma
Recommended Citation
Benitz S, Steep A, Nasser MM, Preall J, Mahajan UM, McQuithey H, Loveless I, Davis ET, Wen HJ, Long DW, Metzler T, Zwernik S, Louw M, Rempinski D, Salas-Escabillas DJ, Brender SM, Song L, Huang L, Theisen BK, Zhang Z, Steele NG, Regel I, Bednar F, and Crawford HC. ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma. Cancer Discov 2024.
Document Type
Article
Publication Date
7-8-2024
Publication Title
Cancer Discov
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.
PubMed ID
38975886
ePublication
ePub ahead of print
