Bone metastasis is a frequent and incurable consequence of advanced prostate cancer (PC). An interplay between disseminated tumor cells and heterogeneous bone resident cells in the metastatic niche initiates this process. Melanoma differentiation associated gene-9 (mda-9/Syntenin/syndecan binding protein) is a prometastatic gene expressed in multiple organs, including bone marrow-derived mesenchymal stromal cells (BM-MSCs), under both physiological and pathological conditions. We demonstrate that PDGF-AA secreted by tumor cells induces CXCL5 expression in BM-MSCs by suppressing MDA-9-dependent YAP/MST signaling. CXCL5-derived tumor cell proliferation and immune suppression are consequences of the MDA-9/CXCL5 signaling axis, promoting PC disease progression. mda-9 knockout tumor cells express less PDGF-AA and do not develop bone metastases. Our data document a previously undefined role of MDA-9/Syntenin in the tumor and microenvironment in regulating PC bone metastasis. This study provides a framework for translational strategies to ameliorate health complications and morbidity associated with advanced PC.
Proceedings of the National Academy of Sciences of the United States of America. 2023 Nov 03 [Epub]
Santanu Maji, Anjan K Pradhan, Amit Kumar, Praveen Bhoopathi, Padmanabhan Mannangatti, Chunqing Guo, Jolene J Windle, Mark A Subler, Xiang-Yang Wang, Oliver J Semmes, Julius O Nyalwidhe, Nitai Mukhopadhyay, Asit Kr Paul, Bryce Hatfield, Michael M Levit, Esha Madan, Devanand Sarkar, Luni Emdad, David J Cohen, Rajan Gogna, Webster K Cavenee, Swadesh K Das, Paul B Fisher
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298., Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507., VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298., Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23238., Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23238., VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298., Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093.