Related Experiment Video
Updated: Oct 1, 2025
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Concerted BAG3 and SIRPα blockade impairs pancreatic tumor growth
Margot De Marco1,2, Vanessa Gauttier3, Sabrina Pengam3
1Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, Baronissi, SA, 84081, Italy.
Abstract:
The BAG3- and SIRPα- mediated pathways trigger distinct cellular targets and signaling mechanisms in pancreatic cancer microenvironment. To explore their functional connection, we investigated the effects of their combined blockade on cancer growth in orthotopic allografts of pancreatic cancer mt4-2D cells in immunocompetent mice. The anti-BAG3 + anti-SIRPα mAbs treatment inhibited (p = 0.007) tumor growth by about the 70%; also the number of metastatic lesions was decreased, mostly by the effect of the anti-BAG3 mAb. Fibrosis and the expression of the CAF activation marker α-SMA were reduced by about the 30% in animals treated with anti-BAG3 mAb compared to untreated animals, and appeared unaffected by treatment with the anti-SIRPα mAb alone; however, the addition of anti-SIRPα to anti-BAG3 mAb in the combined treatment resulted in a > 60% (p < 0.0001) reduction of the fibrotic area and a 70% (p < 0.0001) inhibition of CAF α-SMA positivity. Dendritic cells (DCs) and CD8+ lymphocytes, hardly detectable in the tumors of untreated animals, were modestly increased by single treatments, while were much more clearly observable (p < 0.0001) in the tumors of the animals subjected to the combined treatment. The effects of BAG3 and SIRPα blockade do not simply reflect the sum of the effects of the single blockades, indicating that the two pathways are connected by regulatory interactions and suggesting, as a proof of principle, the potential therapeutic efficacy of a combined BAG3 and SIRPα blockade in pancreatic cancer.
Insights
Combined blockade of BAG3 and SIRPα pathways significantly inhibits pancreatic cancer growth and metastasis. This dual targeting approach enhances anti-tumor immunity by increasing dendritic cells and CD8+ lymphocytes, offering a promising therapeutic strategy.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Distinct cellular targets and signaling mechanisms of BAG3 and SIRPα pathways in pancreatic cancer microenvironment.
- Need to explore the functional connection and combined effects of these pathways.
Purpose of the Study:
- Investigate the effects of combined blockade of BAG3 and SIRPα on pancreatic cancer growth.
- Evaluate the impact on tumor microenvironment, including fibrosis, CAF activation, and immune cell infiltration.
Main Methods:
- Orthotopic allografts of pancreatic cancer mt4-2D cells in immunocompetent mice.
- Treatment with anti-BAG3 and anti-SIRPα monoclonal antibodies (mAbs), individually and in combination.
- Analysis of tumor growth, metastatic lesions, fibrosis, α-SMA expression, dendritic cells (DCs), and CD8+ lymphocytes.
Main Results:
- Combined anti-BAG3 + anti-SIRPα mAbs inhibited tumor growth by ~70% and decreased metastatic lesions.
- Combined treatment significantly reduced fibrosis (>60%) and CAF α-SMA positivity (70%) compared to single treatments.
- Combined blockade markedly increased the infiltration of dendritic cells and CD8+ lymphocytes in tumors.
Conclusions:
- The combined blockade of BAG3 and SIRPα pathways demonstrates synergistic therapeutic efficacy in pancreatic cancer.
- The observed effects suggest interconnected regulatory interactions between the BAG3 and SIRPα pathways.
- This study provides proof of principle for the potential of combined BAG3 and SIRPα blockade as a pancreatic cancer therapy.
