Perivascular interactions in the pre-metastatic niche

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 tumour derived factors, becoming synthetic, migratory, and proliferative. The microenvironmental changes associated with perivascular cell activation increases metastasis. Extravital imaging demonstrated that disseminated tumour cells (DTC) interact with pericytes on extravasation into the lung. We hypothesised 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 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.

Thesis is embargoed until 31 July 2029

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	US National Cancer Institute
Supervisor	Meera Murgai (Supervisor), Cristina Branco (Supervisor) & Nick Orr (Supervisor)