Knockout of MDA-9/Syntenin (SDCBP) expression in the microenvironment dampens tumor-supporting inflammation and inhibits melanoma metastasis

Abstract

Cancer development and progression to metastasis is a complex process, which largely depends on bidirectional communication between tumor cells and their microenvironment. Melanoma differentiation associated gene-9 (mda-9, also known as Syntenin-1, SDCBP), a gene first cloned by our group, is robustly expressed in multiple cancers including melanoma and contributes to invasion and metastasis in a tumor cell-intrinsic manner. However, the role of MDA-9/Syntenin in the tumor cell-extrinsic microenvironment remains unclear even though MDA-9/Syntenin is ubiquitously expressed in most organs that are active metastatic sites for melanoma, e.g., lung, lymph node, brain, and liver. In this study, we explored the effect of environmental mda-9/syntenin expression on melanoma growth and metastasis using multiple immunocompetent animal models, syngeneic B16 xenograft and intravenous B16 mouse model and a genetically engineered mouse (GEM) model of melanoma. Host-deficient expression of mda-9/syntenin in mice negatively impacted on subcutaneously implanted B16 tumor growth and lung metastasis. Absence of MDA-9/Syntenin in the lung microenvironment suppressed tumor growth by modulating in situ Interleukin 17A (IL17A) expression and impaired the recruitment of myeloid derived suppressor cells (MDSCs) and Th17 cells as compared to genetically wild type animals. Additionally, loss of mda-9/syntenin expression in a spontaneous melanoma model (melanocyte-specific pten loss and BrafV600E mutation) significantly delayed tumor initiation and suppressed metastasis to the lymph nodes and lungs. The present study highlights a novel role of mda-9/syntenin in tumor-promoting inflammation and immune suppression. These observations along with other documented roles of MDA-9/Syntenin in cancer and metastasis support the potential relevance of MDA-9/Syntenin in the carcinogenic process and as a target for developing improved therapies by using either genetic or pharmacologic approaches to treat and prevent melanoma and other cancers.

Syntenin-knock out reduces exosome turnover and viral transduction

“…Despite the evidence for the above, but consistent with previous studies in mice by others 45 , 46 , syntenin-KO mice are viable, show no major defects and have normal fertility. This is surprising, given the broad expression of the syntenin protein in fetal and adult human 27 and mouse tissues 47 and the lethality of the corresponding morpholino-mediated knock downs in zebra fish and Xenopus , where syntenin is required for polarized early embryonic cell movements 48 , 49 .…”

MicroRNA‐23a inhibits melanoma cell proliferation, migration, and invasion in mice through a negative feedback regulation of sdcbp and the MAPK/ERK signaling pathway

“…In addition, SDCBP has also been reported to be related with cell migration, invasiveness and pseudopodia formation, all of which were connected with tumor metastasis . Swadesh et al also examined the potential role of SDCBP in melanoma and concluded that dysregulated SDCBP may function as a negatively regulator of melanoma invasion and metastasis . To sum up, our study suggested that miR‐23a could repress the development and progression of melanoma through the down‐regulation of SDCBP.…”

A syntenin-deficient microenvironment educates AML for aggressiveness

“…Tumor-stroma interactions play a prominent role in the evolution of cancers. In contrast with the role of host-syntenin in melanoma progression 22 , we here provide evidence that leukemic blasts confronted with a syntenin-negative environment acquire a cell-autonomous advantage and aggressiveness.…”

“…In comparison, the impact on tumor development resulting from syntenin suppression in the tumor microenvironment remains under-explored. Syntenin-deficiency of the host was shown to reduce melanoma metastasis, by dampening tumor-supporting inflammation 22 .…”