Pericyte derived lipids alter disseminating tumor cell fate decisions

Authors

• T McErlain
• M Glass
• E McCulla
• L Ziemer
• C Branco
• M Murgai

Abstract

Metastasis accounts for 90% of cancer related mortality and is aided by the formation of a pre-metastatic niche. Perivascular cells, including pericytes, initiate development of a pre-metastatic microenvironment upon activation by circulating tumor derived factors, becoming synthetic, migratory, and proliferative. The microenvironmental changes associated with perivascular cell activation increases metastasis. Extravital imaging demonstrated that disseminated tumor cells (DTC) interact with pericytes on extravasation into the lung. We hypothesized that direct pericyte-DTC interaction in the early metastatic microenvironment could confer a survival advantage to DTC. Co-culture experiments were used to assess DTC fate after pericyte contact. Primary lung pericytes transfer lipids to metastatic breast tumor cells (4T1), but not to non-metastatic cells (67NR). Gene expression data from metastatic 4T1 cells after direct co-culture with pericytes demonstrated activation of pathways related to syncytium formation. In normal physiology, pericytes act in a syncytium to regulate blood flow by responding to mechanochannel activation induced by changing blood pressure. We hypothesized that direct contact with tumor cells activates mechanosensitive pericytes to initiate lipid transfer. Lipid transfer was dependent on direct contact and mechanosensitive channel inhibitors significantly reduced the transfer of lipids to 4T1 cells. Intracardiac injection of 4T1 cells isolated from co-culture demonstrated increased lung colonization indicated by enrichment in the number of small lesions compared to the monoculture group, and lower proliferation indicated by reduced ki67 status compared to the monoculture group. These data suggest that tumor cells are reprogrammed by direct pericyte contact in the early metastatic lung to aid persistence and colonization.

Scientific Focus Area: Cancer Biology

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