CANCER MICROENVIRONMENT

This includes normalization and decompression of tumour blood vessels to increase cancer perfusion, and the transformation of tumour endothelial cells into so called “High Endothelial Venules” (HEVs). HEVs are entrance portals for lymphocytes and associated with ectopic intratumoral lymph nodes which facilitate T cell priming (Figure 2). We are now seeking to expand these technologies, in particular induction of intratumoral lymph nodes, to advanced and hard-to-treat cancers where current immunotherapies fail.

Figure 2: Tumour (blue) with therapeutically induced HEVs and lymph node structure (red).  Source: Anna Johansson-Percival

We recently discovered the role of pericyte (cells which wrap around and support endothelial cells) differentiation in the processes of tumour blood vessel normalization, tumour perfusion and penetration of anti-tumour immune effector cells. We are now aiming to elucidate mechanisms of pericyte plasticity in cancer.  In this project, we are using genetically modified mouse models to identify key factors that improve vessel patency, and, importantly, drugs which mimic therapeutic effects observed in genetic models.

We have previously shown that chaotic blood vessels and lack of tumour perfusion are critical barriers that limit anti-cancer therapy at the tumour site. These intratumoral parameters are in large part a manifestation of the tumour stroma which includes the newly formed, angiogenic vasculature. Our laboratory seeks to understand molecular mechanisms of stromal remodelling in tumours with the goal to develop improved therapies by modifying the tumour microenvironment.

Specifically, we are studying mouse models of cancer to develop new approaches which exploit the dynamic nature of tumour stroma to reprogram rather than destroy vessels which provides longer lasting antitumor effects, in particular when combined with immune strategies to eliminate cancer cells. In the course of this project fundamental changes in the tumour vascular bed and stroma before and after therapy will be analysed by histology, quantitative PCR and Western Blots. Vascular cells with overexpression or deletion of specific genes will be employed to assess cytoskeletal rearrangements, migration and signalling events. This project aims to identify molecular mechanisms and signalling pathways which define tumour stroma which is permissive for destruction.