Characterization of the mechanism of inflammasome activation in oncogene-induced senescence

The primary purpose of this project is to characterise and manipulate the signalling mechanism of the senescence-associated innate immune pathways, to develop innovative therapeutic strategies.

Cellular senescence is a critical tumour suppressor mechanism triggered in response to oncogenic stresses (oncogene-induced senescence (OIS)) that impairs the propagation of mutated cells (1-3). Cellular senescence is characterised by a robust cell cycle arrest and the senescence-associated secretory phenotype (SASP), a proinflammatory response that reinforces senescence and promotes immune-clearance of senescent cells. The impact of cellular senescence in cancer is a balance between the tumour-suppressive role of the robust cell-cycle arrest and the SASP-mediated immune surveillance, and the negative pro-tumorigenic SASP effect. As the survival of cancer patients spans due to therapeutic improvements, the cumulative negative effect of the cancer-associated senescent cells becomes critical. Thus, controlling cellular senescence and the SASP in cancer is an emerging need. On the core of the senescence program controlling OIS are senescence-associated pattern recognition receptors of the innate immune system. The ultimate goal of this project is to gain mechanistic insight into these senescence-associated innate immune signalling pathways to inform the generation of mouse models of cancer to dissect the balance between the SASP effects and the tumour suppressor role of OIS in vivo.

We have identified an uncharacterized senescence-associated APAF1/CASP-4 non-canonical inflammasome by proximity labelling proteomics combined with phenotypic analysis using loss of function genetics. These results suggested also a mitochondrial involvement in such activation. The PhD candidate will characterize this new mechanism of inflammasome activation by identifying the functional mitochondrial constituent interacting with the APAF1/CASP1-4 complex, and by mapping the subcellular localization of such interaction using high-resolution microscopy. Thus, we will identify the signal molecule activating this new atypical inflammasome in oncogene induced senescence.

Application procedure

Applicants are invited to apply for this PhD studentship funded by CRUK and must hold a first or upper-second class UK honours degree or equivalent. Further information on how to apply can be found on the CRUK Graduate Research and Training website: https://www.ed.ac.uk/cancer-centre/graduate-research-and-training/cancer-research-uk-phd-programme

Application deadline: 12 February 2021