Benitz, Simone, Steep, Alexander, Nasser, Malak, Preall, Jonathan, Mahajan, Ujjwal M, McQuithey, Holly, Loveless, Ian, Davis, Erick T, Wen, Hui-Ju, Long, Daniel W, Metzler, Thomas, Zwernik, Samuel, Louw, Michaela, Rempinski, Donald, Salas-Escabillas, Daniel, Brender, Sydney, Song, Linghao, Huang, Ling, Zhang, Zhenyu, Steele, Nina, Regel, Ivonne, Bednar, Filip, Crawford, Howard C (December 2023) ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma. bioRxiv. (Submitted)
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Abstract
Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells to precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We found 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. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that was largely persistent upon progression to carcinoma. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > neoplasms diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Preall lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 14 December 2023 |
| Date Deposited: | 16 Jan 2024 14:25 |
| Last Modified: | 16 Jan 2024 14:25 |
| PMCID: | PMC10760092 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41398 |
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