Cellular Senescence and Tumour Suppression
Cellular senescence is a failsafe program triggered to permanently arrest and clear potentially harmful damaged cells. Amongst different cellular stresses, oncogenic activation induces a senescence response termed Oncogene Induced Senescence (OIS) that constitutes an efficient barrier to tumour progression. Most non-malignant tumours are enriched in senescent cells, and tumour cells have to mutate and inactivate tumour suppressor pathways in order to evade the senescence program and progress to more malignant stages. However, malignant cells can be induced to senescence with conventional and targeted anticancer therapies, implying that some mechanisms of activation of senescence are still in place. Thus, elucidating pathways activating senescence in the context of tumour suppression has the potential to pave new avenues for anticancer therapies.
The senescence program manifests with changes in cellular organisation, chromatin remodelling and gene expression, such as the induction of a complex secretome. Our group and others reported that the proinflammatory secretome (Senescence Associated Secretory Phenotype or SASP) regulates the initiation and maintenance of senescence and the clearance of the senescent cells by the immune system. We identified the role of the SASP in the regulation of Replicative Senescence and OIS through the IL-8 receptor CXCR2 (Acosta et al. Cell 2008). Thus, the SASP is an intrinsic component of the tumour suppressor program executed by senescence. Recently, we discovered that OIS could be transmitted to naïve normal neighbouring cells in a process denominated paracrine senescence in vitro and in vivo with implications in tumour suppression. Importantly, the regulation of OIS and paracrine senescence by the SASP is tightly regulated by the activation of IL-1 signalling by the inflammasome (Acosta et al. Nat Cell Biol 2013). Thus, understanding the regulation and the activity of the SASP is crucial for the future manipulation in cancer therapies (Acosta et al. Trends Cell. Biol. 2012).
|Juan-Carlos Acosta||Principal Investigator, CRUK Career Development Fellow and UoE Chancellor’s Fellow|
|Andrea Quintanilla||Post Doc|
|Priya Hari||PhD Student|
|Irene Fernandez||PhD Student|
|Rachel White||Research Assistant|
|Nuria Tarrats||Post Doc|
|Flora Dix||PhD Student|
Oncogene induced senescence, paracrine senescence, SASP, senescence associated microenvironment, tumour suppression, tumour associated inflammation
Cell and molecular biology, DNA, RNA and protein analysis methods, senescence assays