Antibody-mediated blockade for galectin-3 binding protein in tumor secretome abrogates PDAC metastasis
Yeon-Sook Choi1, Myung Ji Kim1, Eun A Choi1
1Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea.
Abstract:
The major challenges in pancreatic ductal adenocarcinoma (PDAC) management are local or distant metastasis and limited targeted therapeutics to prevent it. To identify a druggable target in tumor secretome and to explore its therapeutic intervention, we performed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis of tumors obtained from a patient-derived xenograft model of PDAC. Galectin-3 binding protein (Gal-3BP) is identified as a highly secreted protein, and its overexpression is further validated in multiple PDAC tumors and primary cells. Knockdown and exogenous treatment of Gal-3BP showed that it is required for PDAC cell proliferation, migration, and invasion. Mechanistically, we revealed that Gal-3BP enhances galectin-3-mediated epidermal growth factor receptor signaling, leading to increased cMyc and epithelial-mesenchymal transition. To explore the clinical impact of these findings, two antibody clones were developed, and they profoundly abrogated the metastasis of PDAC cells in vivo. Altogether, our data demonstrate that Gal-3BP is an important therapeutic target in PDAC, and we propose its blockade by antibody as a therapeutic option for suppressing PDAC metastasis.
Insights
Researchers identified Galectin-3 binding protein (Gal-3BP) as a key driver of pancreatic cancer metastasis. Blocking Gal-3BP with antibodies shows promise in preventing cancer spread, offering a new therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Molecular Biology
- Proteomics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in management due to metastasis and a lack of effective targeted therapies.
- Identifying novel therapeutic targets within the tumor secretome is crucial for developing effective anti-metastatic strategies.
Purpose of the Study:
- To identify druggable targets in the PDAC secretome and evaluate their therapeutic potential for preventing metastasis.
- To investigate the role of Galectin-3 binding protein (Gal-3BP) in PDAC progression and metastasis.
Main Methods:
- Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis of patient-derived xenograft models.
- Validation of Gal-3BP overexpression in PDAC tumors and cells.
- In vitro knockdown and exogenous treatment experiments to assess Gal-3BP function.
- In vivo studies using antibody clones targeting Gal-3BP to evaluate therapeutic efficacy.
Main Results:
- Galectin-3 binding protein (Gal-3BP) was identified as a highly secreted protein overexpressed in PDAC.
- Gal-3BP knockdown inhibited PDAC cell proliferation, migration, and invasion.
- Gal-3BP was found to enhance galectin-3-mediated epidermal growth factor receptor signaling, promoting cMyc expression and epithelial-mesenchymal transition.
- Developed antibody clones targeting Gal-3BP significantly abrogated PDAC metastasis in vivo.
Conclusions:
- Galectin-3 binding protein (Gal-3BP) is a critical mediator of PDAC metastasis.
- Antibody-mediated blockade of Gal-3BP represents a promising therapeutic strategy for suppressing PDAC progression and metastasis.
