Exploring the microclot-driven pre-metastatic niche

: live imaging studies in zebrafish larvae

Abstract

During metastasis, many tumour cells move into the blood vessels of the host, where they can rapidly disperse to multiple sites within the body, distant from the primary tumour. Once these cells have reached the capillaries of a distant organ that might be suitable for the establishment of a secondary tumour, they must arrest and extravasate. The site of this arrest is known as the pre-metastatic niche. As the pre-metastatic niche develops, tumour cells recruit a range of host cells, including platelets and innate immune cells, which may then support cancer survival, extravasation and metastasis. The drivers and dynamics of these recruitment events are still unclear. Here, I have used human and zebrafish cancer cell grafts to develop a larval zebrafish model of the pre-metastatic niche. Taking advantage of the optical translucency of zebrafish larvae I investigate the roles of platelets, coagulation, and innate immune cells in the pre-metastatic niche using confocal live imaging.

I find that the presence of activated thrombocytes and fibrin leads to the recruitment of macrophages and neutrophils to cancer cells within the larval vasculature, and that the presence of these innate immune cells appears essential for cancer cell extravasation. Further, I discovered a link between fibrin association with cancer cells and the polarisation state of macrophages. Loss of fibrin appears to drive a pro-inflammatory, M1-like phenotype which inhibits metastatic behaviour in grafted cancer cells. My data show the importance of haemostatic pathways in metastasis and implicate innate immune cell interactions with fibrin and platelets as fundamental in this process, and so worth of further study as potential targets for clinical interventions in cases of metastatic cancer.

Date of Award	9 May 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Paul B Martin (Supervisor) & Catherine D Nobes (Supervisor)