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.
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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.
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Published |
2025-1-9
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DOI |
10.1158/2767-9764.CRC-24-0491
|
PII |
750890
|
PMID |
39785683
|
Resource |
Human and Animal Cells |
KP4(RCB1005) |