title: 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.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Anjan K
authors.initials: AK
authors.lastname: Pradhan
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Bhoopathi
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Talukdar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Subler
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Jolene J
authors.initials: JJ
authors.lastname: Windle
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D053676:Syntenins / Q000235:genetics* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; C484513:Sdcbp protein, mouse; D053676:Syntenins; C577686:interleukin-6, mouse; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: interleukin -17A (IL-17A); melanoma differentiation associated gene-9/syntenin (mda-9/syntenin); myeloid-derived tumor suppressor cells (MDSC); syndecan binding protein (SDCBP); tumor microenvironment