Pharmacological inhibition of MDA-9/Syntenin blocks breast cancer metastasis through suppression of IL-1 beta
Menée à l'aide de modèles de cancers mammaires, cette étude met en évidence un mécanisme par lequel l'inhibition pharmacologique de la synténine (MDA-9) bloque le processus métastatique via la suppression de l'interleukine IL-1 bêta
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.Melanoma differentiation associated gene-9 (MDA-9), Syntenin-1, or syndecan binding protein is a differentially regulated prometastatic gene with elevated expression in advanced stages of melanoma. MDA-9/Syntenin expression positively associates with advanced disease stage in multiple histologically distinct cancers and negatively correlates with patient survival and response to chemotherapy. MDA-9/Syntenin is a highly conserved PDZ-domain scaffold protein, robustly expressed in a spectrum of diverse cancer cell lines and clinical samples. PDZ domains interact with a number of proteins, many of which are critical regulators of signaling cascades in cancer. Knockdown of MDA-9/Syntenin decreases cancer cell metastasis, sensitizing these cells to radiation. Genetic silencing of MDA-9/Syntenin or treatment with a pharmacological inhibitor of the PDZ1 domain, PDZ1i, also activates the immune system to kill cancer cells. Additionally, suppression of MDA-9/Syntenin deregulates myeloid-derived suppressor cell differentiation via the STAT3/interleukin (IL)-1β pathway, which concomitantly promotes activation of cytotoxic T lymphocytes. Biologically, PDZ1i treatment decreases metastatic nodule formation in the lungs, resulting in significantly fewer invasive cancer cells. In summary, our observations indicate that MDA-9/Syntenin provides a direct therapeutic target for mitigating aggressive breast cancer and a small-molecule inhibitor, PDZ1i, provides a promising reagent for inhibiting advanced breast cancer pathogenesis. All study data are included in the article and SI Appendix.