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SUMMARY:Imaging and targeting cancer\; the multitasking Focal Adhesion Kin
 ase controls cancer cell polarization and immune evasion - Margaret Frame\
 ; Edinburgh Cancer Research Centre
DTSTART:20151029T130000Z
DTEND:20151029T140000Z
UID:TALK59820@talks.cam.ac.uk
CONTACT:Neil Bennett
DESCRIPTION:The behavior of tumors can be ascribed to both cell-autonomous
  and non cell-autonomous traits. The integrin effector protein Focal Adhes
 ion Kinase (FAK)\, which is mis-regulated in cancer\, is a self-regulating
  scaffold/ kinase that controls molecular protein complex assembly at adhe
 sion 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 prop
 ortion of which are cancer cells. It is in this context that I will descri
 be a completely new function of FAK in driving anti-tumor immune evasion. 
  Specifically\, the activity of nuclear-targeted FAK in cancer cells drive
 s recruitment and retention of intra-tumoral regulatory T-cells (Tregs) by
  transcriptionally regulating chemokine and cytokine ligand-receptor netwo
 rks\, crucially including transcription of Ccl5 and TGFb2. In turn\, these
  changes inhibit antigen-primed cytotoxic CD8+ T-cell activity in the tumo
 r microenvironment\, permitting survival and growth of FAK-expressing tumo
 rs.  We show that immune evasion requires nuclear FAK’s catalytic activi
 ty and and a small molecule FAK kinase inhibitor\, VS-4718\, which is curr
 ently in clinical development\, drives depletion of Tregs and permits CD8+
  T-cell-mediated tumor clearance.  It is therefore likely that FAK inhibit
 ors may trigger both inhibition of polarization and invasion\, and promote
  immune-mediated negative pressure on tumours\, potentially providing prev
 iously 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.
LOCATION:CRUK CI Lecture Theatre
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