Imaging and targeting cancer; the multitasking Focal Adhesion Kinase controls cancer cell polarization and immune evasion

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• Margaret Frame; Edinburgh Cancer Research Centre
• Thursday 29 October 2015, 13:00-14:00
• CRUK CI Lecture Theatre.

If you have a question about this talk, please contact Neil Bennett.

The behavior of tumors can be ascribed to both cell-autonomous and non cell-autonomous traits. The integrin effector protein Focal Adhesion Kinase (FAK), which is mis-regulated in cancer, is a self-regulating scaffold/ kinase that controls molecular protein complex assembly at adhesion sites and at other sub-cellular locale. Adhesion-linked complexes ‘built’ by FAK typically regulate processes associated with adhesion and actin dynamics, and consequently cancer cell polarization and invasion. However, the tumor niche is composed of multiple cell types, only a proportion of which are cancer cells. It is in this context that I will describe a completely new function of FAK in driving anti-tumor immune evasion. Specifically, the activity of nuclear-targeted FAK in cancer cells drives recruitment and retention of intra-tumoral regulatory T-cells (Tregs) by transcriptionally regulating chemokine and cytokine ligand-receptor networks, crucially including transcription of Ccl5 and TGFb2. In turn, these changes inhibit antigen-primed cytotoxic CD8 T-cell activity in the tumor microenvironment, permitting survival and growth of FAK -expressing tumors. We show that immune evasion requires nuclear FAK ’s catalytic activity and and a small molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, drives depletion of Tregs and permits CD8 T-cell-mediated tumor clearance. It is therefore likely that FAK inhibitors may trigger both inhibition of polarization and invasion, and promote immune-mediated negative pressure on tumours, potentially providing previously unrecognized therapeutic benefit. I will also describe some of our on-going efforts to image cancer in the niche, including via multi-modal label-free Raman-based techniques.

This talk is part of the Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer series.

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