Pharmacological inhibition of MDA-9/Syntenin blocks breast cancer metastasis through suppression of IL-1β
Abstract
Metastasis is a leading cause of breast cancer-associated death. MDA-9/Syntenin expression is elevated and contributes at multiple nodal points in the metastatic process. Inhibition of MDA-9/Syntenin using a pharmacological inhibitor (PDZ1i), which blocks protein–protein interactions, suppresses metastasis in syngeneic mouse and human xenograft models. PDZ1i therapy robustly constrains breast cancer metastasis in syngeneic animals by inhibiting tumor cell-derived interleukin-1β secretion through deactivation of STAT3 and reducing infiltration of immune suppressor cells in the metastatic niche. Enhanced antitumor immunity correlates with expansion of interferon-γ–expressing T cells and conversion of the immunosuppressive microenvironment into an immunostimulatory tumor environment. Collectively, our findings highlight the essential function of MDA-9/Syntenin in immune tolerance, documenting a promising therapeutic strategy selectively targeting breast cancer metastasis.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 20, 2021
- Source ID
- 10.1073/pnas.2103180118
Entities
People
- Anjan K. Pradhan
- Chunqing Guo
- Devanand Sarkar
- Joseph W Landry
- Lorraine Colon-Cartagena
- Luni Emdad
- Michael Idowu
- Padmanabhan Mannangatti
- Paul B Fisher
- Praveen Bhoopathi
- Santanu Maji
- Sarmistha Talukdar
- Swadesh K. Das
- Webster Cavenee
- Xiang-Yang Wang
Organizations
- Congressionally Directed Medical Research Programs
- National Cancer Institute
- National Foundation for Cancer Research
- University of California, San Diego
- Virginia Commonwealth University