Perivascular interactions in the pre-metastatic niche

Primary lung pericytes transfer lipids to metastatic breast tumour 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 hypothesised that direct contact with tumour cells activates mechanosensitive pericytes to initiate lipid transfer. Lipid transfer was dependent on direct contact and was not observed with transwell assays. Mechanosensitive calcium channel inhibitors significantly reduced the transfer of lipids to 4T1 cells.

Intracardiac injection of 4T1 cells isolated from co-culture demonstrated increased lung colonisation 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 tumour cells are reprogrammed by direct pericyte contact in the early metastatic lung to aid persistence and colonisation.<br><br><i>Thesis is embargoed until 31 July 2029</i><br>