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Updated: Jun 6, 2026
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
CA19-9 induces microenvironment remodeling in pancreatic ductal adenocarcinoma
Jasper Hsu1, Hyemin Song1, Satoshi Ogawa1
1Salk Institute for Biological Studies, La Jolla, California, USA.
Abstract:
Durable therapeutic efficacy remains a major barrier to improving outcomes for patients with pancreatic ductal adenocarcinoma (PDAC). An immunosuppressive tumor microenvironment (TME) is a hallmark of PDAC and has been demonstrated to be a dominant driver of therapeutic resistance. The aberrant glycan CA19-9 is prevalent in PDAC and drives tumor progression, but the paracrine mechanisms by which it contributes to TME remodeling are unknown. To address this, we mapped TME changes and performed functional analyses using a genetically engineered mouse model (GEMM) harboring KrasG12D mutation and inducible CA19-9 expression. Elevation of CA19-9 led to expansion of antigen-presenting cancer associated fibroblasts (apCAFs) and regulatory T cells (Tregs), which can drive immunosuppression. Antibody blockade of CA19-9 resulted in significant restoration of normal histology and decreased apCAF and Treg populations. We dissected the paracrine signaling mechanisms that drive this TME remodeling in vitro using mouse and human organoid mono- and co-culture models as well as in vivo using GEMMs and syngeneic orthotopic transplantation models. CA19-9 induced IL1a and TGFb expression, reprogramming pancreatic mesothelial cells into apCAFs in vitro, which in turn directly ligated naïve Cd4+ T cells resulting in Treg differentiation in co-cultures. Antibody blockade of IL1a and TGFb in mice led to reduced apCAF and Treg differentiation. We previously reported that CA19-9 modification of the secreted Fbln3 protein increased Egfr engagement and now find that the induction of IL1a and TGFb expression by CA19-9 is dependent on Fbln3 hyperactivation of EGFR signaling. Genetic depletion of Fbln3 led to reduced tumor progression and increased Cd8+ T cell infiltration in mice. Together these findings identify a previously unknown signaling axis driving immunosuppressive phenotypes in PDAC, uncovering multiple potential nodes to relieve the immunosuppressive pressures within the PDAC TME.
Insights
Pancreatic cancer
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits an immunosuppressive tumor microenvironment (TME), contributing to therapeutic resistance.
- The aberrant glycan CA19-9 is associated with PDAC progression, but its role in TME remodeling is unclear.
Purpose of the Study:
- To elucidate the paracrine mechanisms by which CA19-9 remodels the PDAC TME.
- To identify potential therapeutic targets for overcoming immunosuppression in PDAC.
Main Methods:
- Utilized a genetically engineered mouse model (GEMM) with KrasG12D mutation and inducible CA19-9 expression.
- Employed in vitro organoid co-culture systems and in vivo transplantation models.
- Investigated signaling pathways involving IL1a, TGFb, Fbln3, and EGFR.
Main Results:
- CA19-9 elevation expanded immunosuppressive antigen-presenting cancer-associated fibroblasts (apCAFs) and regulatory T cells (Tregs).
- CA19-9 induced IL1a and TGFb, reprogramming mesothelial cells into apCAFs, which promoted Treg differentiation.
- Fbln3-mediated EGFR signaling was critical for CA19-9-induced IL1a and TGFb expression.
Conclusions:
- Identified a novel signaling axis (CA19-9/Fbln3/EGFR/IL1a/TGFb) driving immunosuppression in PDAC.
- Antibody blockade of CA19-9, IL1a, or TGFb reduced immunosuppressive cell populations.
- Targeting this axis offers potential therapeutic strategies to enhance anti-tumor immunity in PDAC.
