Work Package 1: Identify approaches to block death receptor-induced tumour cell motility/invasion.
While the signalling complex that drives cell death upon activation of death receptors (DR) is well characterised, the signalling complex that induce tumour cell motility upon death receptor activation are poorly understood. WP1 determines:
The molecular DISC composition that switches the output from death signalling to the non-canonical, motility/invasion signalling
Develop small molecule inhibitors to block DR-induced migratory signalling
Develop inhibitors to block non-death DR signalling
Work Package 2: Determine strategies to block death ligand-induced tumour immune tolerance.
Death ligands can inhibit effector immune cell activation and expansion. WP2 determines whether this function plays a role in the context of tumour immune editing by determining the role of DR and DL signalling in sculpting natural killer (NK) cell functions, NK T cell functions, macrophage polarisation and effector functions in the tumour microenvironment.
Work Package 3: Identify mechanisms to activate intracellular DR (Death Receptor)-mediated death signalling.
DR-mediated cell death signalling is one of the few mechanisms that can be exploited to kill cancer cells without triggering DNA damage and unpredictable mutations. While it is emerging that surface-expressed DRs trigger a broad spectrum of cellular responses that limits their utility in cancer therapy, induction of cell death via intracellular DR-activation appears to be a promising avenue. WP3 determines:
The mechanism of intracellular DR activation in response to cellular stresses.
Develop a therapeutic strategy to trigger intracellular cell death signal transduction by DRs.