Tuveson, David, Tonelli, Claudia, Deschenes, Astrid, Gaeth, Victoria, Jensen, Amanda, Vithlani, Nandan, Yao, Melissa, Zhao, Zhen, Park, Youngkyu (October 2024) Ductal pancreatic cancer interception by FGFR2 abrogation. bioRxiv. ISSN 2692-8205 (Public Dataset) (Submitted)
Abstract
Activating KRAS mutations are a key feature of pancreatic ductal adenocarcinoma (PDA) and drive tumor initiation and progression. However, mutant KRAS by itself is weakly oncogenic. The pathways that cooperate with mutant KRAS to induce tumorigenesis are less-defined. Analyzing organoids and murine and human pancreatic specimens, we found that the receptor tyrosine kinase FGFR2 was progressively up-regulated in mutant KRAS-driven metaplasia, pre-neoplasia and Classical PDA. Using genetic mouse models, we showed that FGFR2 supported mutant KRAS-driven transformation of acinar cells by promoting proliferation and MAPK pathway activation. FGFR2 abrogation significantly delayed tumor formation and extended the survival of these mice. Furthermore, we discovered that FGFR2 collaborated with EGFR and dual blockade of these receptor signaling pathways significantly reduced mutant KRAS-induced pre-neoplastic lesion formation. Together, our data have uncovered a pivotal role for FGFR2 in the early phases of pancreatic tumorigenesis, paving the way for future therapeutic applications of FGFR2 inhibitors for pancreatic cancer interception.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Tuveson lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 18 October 2024 |
| Date Deposited: | 18 Oct 2024 14:12 |
| Last Modified: | 18 Oct 2024 14:12 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/41709 |
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