RRC ID 82714
Author Wu C, von Schalscha T, Sansanwal D, Qian C, Jiang Q, Shepard RM, Wettersten HI, McCormack S, Weis SM, Cheresh DA.
Title Targeting pancreatic cancer cell stemness by blocking fibronectin-binding integrins on cancer-associated fibroblasts.
Journal Cancer Res Commun
Abstract Cancer-associated fibroblasts (CAF) generate an extracellular matrix (ECM) which provides a repository for factors that promote pancreatic cancer progression. Here, we establish that CAF contribution to pancreatic tumor initiation, i.e. stemness, depends on fibronectin (FN) as a scaffold required for assembly of a collagen-containing fibrotic ECM with a critical dependence on the FN-binding integrins, α5β1 and αvβ3. CAF matrix assembly can be prevented by knockdown of FN, ITGA5, or ITGB3, or by a bispecific antibody with dual recognition of α5β1 and αvβ3 that can also destabilize a pre-existing matrix. In mice, the ability of CAFs to produce a stiff collagenous matrix and accelerate tumor initiation can be blocked by knockdown of FN or FN-binding integrins, or systemic treatment with the α5β1/αvβ3 bispecific antibody. Together, these results reveal that dual targeting of the FN-binding integrins α5β1/αvβ3 can block the ability of CAFs and their matrix from enhancing pancreatic cancer stemness and progression.
Published 2025-1-9
DOI 10.1158/2767-9764.CRC-24-0491
PII 750890
PMID 39785683
Resource
Human and Animal Cells KP4(RCB1005)