Tonelli, Claudia, Deschênes, Astrid, Gaeth, Victoria A, Jensen, Amanda, Vithlani, Nandan, Yao, Melissa A, Zhao, Zhen, Park, Youngkyu, Tuveson, David A (April 2025) FGFR2 Abrogation Intercepts Pancreatic Ductal Adenocarcinoma Development. Cancer Research. ISSN 0008-5472 (Public Dataset)
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. Defining the pathways that cooperate with mutant KRAS to induce tumorigenesis could identify prevention and treatment strategies. 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-cancerous lesions and classical PDA. In genetic mouse models, FGFR2 inactivation impeded mutant KRAS-driven transformation of acinar cells by reducing proliferation and MAPK pathway activation. FGFR2 abrogation significantly delayed tumor formation and extended the survival of these mice. Furthermore, FGFR2 collaborated with EGFR and dual blockade of these receptor signaling pathways significantly reduced mutant KRAS-induced pre-cancerous lesion formation. Together, these 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 Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service CSHL Cancer Center Shared Resources > Bioinformatics Service CSHL Cancer Center Shared Resources > Flow Cytometry Service CSHL Cancer Center Shared Resources > Microscopy Service CSHL Cancer Center Shared Resources > Sequencing Technology & Analysis Service CSHL labs > Tuveson lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2 April 2025 |
| Date Deposited: | 02 Apr 2025 12:07 |
| Last Modified: | 02 Apr 2025 12:07 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/41840 |
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