The role of macrophages and pericytes in shaping the perivascular niche and supporting cancer progression

Primary supervisor: James Arnold, King’s College London

Secondary supervisor: Kairbaan Hodivala-Dilke, Queen Mary University of London

Project

Despite the many pro-tumoral functions that have been described for the various stromal populations in cancer, it is becoming apparent that these cells are not working alone, but instead in concert with one another as part of a wider network of cross-communication to facilitate disease progression. Tumour associated macrophages (TAMs) have been implicated in a variety of pro-tumoral processes and are polarized by signals in the tumour microenvironment (TME) to adopt a range of functionally distinct subsets to perform specialized tasks. Perivascular TAMs are a distinct subset that spatially reside proximal to blood vessels in cancer. We have recently demonstrated that these cells form collaborative CCR5-dependent nest structures which associate with immune exclusion in cancer (Anstee et al., 2023 Developmental Cell). Perivascular TAMs also help shape the niche and interact closely with mesenchymal populations where they can support the expansion of pericyte-like cells during cancer progression (Opzoomer et al., Science Advances, 2021). The perivascular niche is dynamic and the stromal cells in this region are important for supporting tumour progression. However, our knowledge of the communication axes and mechanisms of action associated with immune-mesenchymal crosstalk in the perivascular space is still under-developed and could provide new therapeutic opportunities for treating cancer.

The current project will capitalize on the expertise and models generated for studying TAMs (Prof Arnold lab at King’s College London) and pericytes (Prof Hodivala-Dilke lab at Queen Mary University of London) to explore the communications between these cells and their role in cancer progression. The project will capitalize on single cell RNAseq and spatial transcriptomic datasets from a spontaneous in vivo model of breast cancer to characterize the communication between these cells. The project will then utilize in vivo models of cancer, depletion and knockout approaches to discover and validate new mechanisms of action. Ex vivo, tumour tissue will be investigated to explore the mechanistic basis for any anti-tumour control observed. There will be a particular focus on using high dimensional flow cytometry and imaging techniques to investigate changes in the TME. The project will also explore live cell imaging within the TME to try to capture the interactions and changes identified in a temporal manner. The project is anticipated to involve the following procedures: in vivo models of cancer, flow cytometry, confocal microscopy, intravital microscopy, transcriptomics, qRT PCR, cloning, cell culture, drug treatment approaches.

Overarching objectives:

1. Characterise the pericyte and TAM interactions during cancer development
2. Validate mechanisms of action using genetic approaches and investigate their role in cancer progression
3. Capitalise on the knowledge from objectives 1&2 into investigate translatable therapeutic approaches to target the perivascular niche and the mechanism(s) of action.

Candidate background

The project would be suitable for a student with a background in immunology and/or biomedical sciences. An interest in tumour microenvironment, immunology and immunotherapy is vital.

Potential Research Placements

1. Kairbaab Hodivala-Dilke, Barts Cancer Institute, Queen Mary University of London
2. Anita Grigoriadis, Comprehensive Cancer Centre, King’s College London
3. Esther Arwert, Institute of Cancer Research

References

1. Anstee, J.E., et al. (2023) LYVE-1+ macrophages form a collaborative CCR5-dependent perivascular niche that influences chemotherapy responses in murine breast cancer. Developmental Cell. 58:17
2. Opzoomer, et al. (2021) Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression. Science Advances. 7:45.
3. Wong, P.P. et al. (2020) Cancer burden is controlled by Mural Cell-β3-integrin regulated crosstalk with tumor cells. Cell, 181:1346.
4. Lechertier, T. (2020) Pericyte FAK negatively regulates Gas6/Axl signaling to suppress tumor angiogenesis and tumour growth. Nature Communications. 11:2810.
5. Muliaditan, T., et al. (2018) Macrophages are exploited from an innate wound healing response to facilitate metastases in cancer. Nature Communications, 9:2951.