Skeleton and liver are preferred organs for cancer dissemination in metastatic melanoma negatively impacting quality of life, therapeutic success and overall survival rates. At the target organ, the local microenvironment and cell-to-cell interactions between invading and resident stromal cells constitute critical components during the establishment and progression of metastasis. Mesenchymal stem cells (MSCs) possess, in addition to their cell progenitor function, a secretory capacity based on cooperativity with other cell types in injury sites including primary tumors (PT). However, their role at the target organ microenvironment during cancer dissemination is not known. We report that local MSCs, acting as pericytes, regulate the extravasation of melanoma cancer cells (MCC) specifically to murine bone marrow (BM) and liver. Intra-arterially injected wild-type MCC fail to invade those selective organs in a genetic model of perturbed pericyte coverage of the vasculature (PDGF-Bret/ret), similar to CD146-deficient MCC injected into wild type mice. Invading MCC interact with resident MSCs/pericytes at the perivascular space through co-expressed CD146 and Sdf-1/CXCL12-CXCR4 signaling. Implanted engineered bone structures with MSCs/pericytes deficient of either Sdf-1/CXCL12 or CD146 become resistant to invasion by circulating MCC. Collectively, the presence of MSCs/pericytes surrounding the target organ vasculature is required for efficient melanoma metastasis to BM and liver. What's new? While in primary tumors Mesenchymal Stem Cells (MSCs) possess a cell progenitor function and secretory capacity based on intercellular cooperativity, their role in the target organ microenvironment during cancer dissemination remains unknown. This study shows that MSC/pericytes function as sentinels regulating cancer cell dissemination, with a differential effect during intravasation at the primary tumor and extravasation at the target organ. The molecular mechanisms, cellular players, and locations identified during the establishment of melanoma metastasis to bone marrow and liver may help design novel therapeutic strategies for reducing engraftment by closing the gate through which metastatic cells enter the target organ.
- mesenchymal stem cells (MSCs)
- metastatic melanoma
ASJC Scopus subject areas
- Cancer Research