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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2024)

Pancreatic cancer is characterized by a dense fibrotic stroma, consisting of cancer-associated fibroblasts (CAFs), immune cells, and extracellular matrix (ECM) that promote tumor growth and treatment resistance. CAFs secrete and organize on their surface ECM proteins, including fibronectin (FN) which coordinates the assembly of collagen fibrils that promote matrix stiffness. Since CAFs are a major contributor to fibrosis and the progression of pancreatic cancer, novel approaches to target their function could have a significant impact on patient outcome. This research demonstrates that the ability of pancreatic cancer cells to initiate tumors in mice is greatly enhanced by co-injection of CAFs. Targeting FN via FN-binding integrins α5β1 and αvβ3 that are highly expressed on CAFs disrupts CAF-induced fibrosis, decreases tumor stiffness, and prevents the initiation of pancreas tumors in mice. These results highlight the therapeutic potential of targeting fibronectin-binding integrins, α5β1 and αvβ3, on CAFs to disrupt the fibrotic stroma in pancreatic cancer.

    Cover page: Fibronectin-Binding Integrins Alpha-5 Beta-1 and Alpha-v Beta-3 on Cancer-Associated Fibroblasts Block Fibronectin Collagen Matrix Assembly, Tumor Initiation and Tissue Stiffness
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2025)

    Abstract

    Cancer-associated fibroblasts (CAF) generate an extracellular matrix (ECM) which provides a repository for factors that promote pancreatic cancer progression. In this study, 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, integrin α5, or integrin β3 or by a bispecific antibody with dual recognition of α5β1 and αvβ3 that can also destabilize a preexisting 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 and αvβ3, can block the ability of CAFs and their matrix to enhance pancreatic cancer stemness and progression.

    Significance

    Simultaneous targeting of two integrins that function as receptors for FN, a protumor ECM protein, can prevent fibroblasts from supporting the malignant behavior of pancreatic cancer cells.
      Cover page: Targeting Pancreatic Cancer Cell Stemness by Blocking Fibronectin-Binding Integrins on Cancer-Associated Fibroblasts
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