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BAG3 induces fibroblasts to release key cytokines involved in pancreatic cell migration
Beatrice Dufrusine1,2, Verena Damiani1,2, Emily Capone1,2
1Department of Innovative Technologies in Medicine and Dentistry, University of Chieti-Pescara, Chieti, Italy.
Abstract:
Pancreatic ductal adenoma carcinoma (PDAC) is considered one of the deadliest solid cancers as it is usually diagnosed in advanced stages and has a poor response to treatment. The enormous effort made in the last 2 decades in the oncology field has not led to significant progress in improving early diagnosis or therapy for PDAC. The stroma of PDAC plays an active role in tumour initiation and progression and includes immune cells and stromal cells. We previously reported that Bcl2-associated athanogene (BAG3) secreted by PDAC cells activates tumour-associated macrophages to promote tumour growth. The disruption of this tumour-stroma axis by the anti-BAG3 H2L4 therapeutic antibody is sufficient to delay tumour growth and limit metastatic spreading in different PDAC preclinical models. In the present study, we examined the role of BAG3 to activate human fibroblasts (HF) in releasing cytokines capable of supporting tumour progression. Treatment of fibroblasts with recombinant BAG3 induced important changes in the organisation of the cytoskeleton of these cells and stimulated the production of interleukin-6, monocyte chemoattractant protein-1/C-C motif chemokine ligand 2, and hepatocyte growth factor. Specifically, we observed that BAG3 triggered a depolymerisation of microtubules at the periphery of the cell while they were conserved in the perinuclear area. Conversely, the vimentin-based intermediate filaments increased and spread to the edges of the cells. Finally, the conditioned medium (CM) collected from BAG3-treated HF promoted the survival, proliferation, and migration of the PDAC cells. Blocking of the PDAC-fibroblast axis by the H2L4 therapeutic anti-BAG3 antibody, resulted in inhibition of cytokine release and, consequently, the inhibition of the migratory phenotype conferred by the CM to PDAC cells.
Insights
Pancreatic ductal adenocarcinoma (PDAC) progression is fueled by the protein BAG3, which activates fibroblasts to release tumor-promoting cytokines. Targeting this BAG3-fibroblast axis with an anti-BAG3 antibody inhibits tumor growth and spread.
Area of Science:
- Oncology
- Cancer Biology
- Tumor Microenvironment
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited therapeutic options.
- The tumor stroma, including fibroblasts, significantly influences PDAC initiation and progression.
- Previous work identified Bcl2-associated athanogene (BAG3) secreted by PDAC cells activating tumor-associated macrophages.
Purpose of the Study:
- To investigate the role of BAG3 in activating human fibroblasts (HF) to release cytokines that support PDAC progression.
- To elucidate the molecular mechanisms by which BAG3 affects fibroblast cytoskeletal organization.
- To evaluate the therapeutic potential of targeting the PDAC-fibroblast axis using an anti-BAG3 antibody.
Main Methods:
- Treatment of human fibroblasts with recombinant BAG3.
- Analysis of fibroblast cytoskeletal organization (microtubules and vimentin).
- Quantification of cytokine release (IL-6, MCP-1/CCL2, HGF) from treated fibroblasts.
- Assessment of conditioned medium (CM) from treated fibroblasts on PDAC cell survival, proliferation, and migration.
- Inhibition studies using the anti-BAG3 H2L4 antibody.
Main Results:
- Recombinant BAG3 induced significant changes in fibroblast cytoskeleton, including microtubule depolymerization and vimentin redistribution.
- BAG3 stimulated the release of pro-tumorigenic cytokines IL-6, MCP-1/CCL2, and HGF from fibroblasts.
- Conditioned medium from BAG3-activated fibroblasts enhanced PDAC cell survival, proliferation, and migration.
- The anti-BAG3 H2L4 antibody blocked BAG3-induced cytokine release and abrogated the pro-migratory effects of the conditioned medium on PDAC cells.
Conclusions:
- BAG3 secreted by PDAC cells activates fibroblasts, promoting a pro-tumorigenic microenvironment.
- BAG3 modulates fibroblast cytoskeletal dynamics, leading to the release of key growth and migration factors.
- Targeting the BAG3-fibroblast interaction with the H2L4 antibody represents a promising therapeutic strategy for PDAC by disrupting tumor-stroma communication.
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