MDA-9/Syntenin in the tumor and microenvironment defines prostate cancer bone metastasis

Bone metastasis is a frequent and incurable consequence of advanced prostate can-cer (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 prolif-eration 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 metas-tasis. This study provides a framework for translational strategies to ameliorate health complications and morbidity associated with advanced PC.