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Research Interests

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 organization, 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. However, the complex cocktail of factors that constituted the SASP have paradoxical tumour suppressive and promoting effects, thus, understanding the switch between tumour suppressive to promoting activity is crucial for the future manipulation of the SASP in cancer therapies (Acosta et al. Trends Cell. Biol. 2012).


1. We aim to identify new pathways regulating the activation of the SASP, to discover the components of the SASP with intrinsic or non-cell autonomous tumour suppressive role and to gain insight into what causes the switch from tumour suppressive to promoting activities.

2. Our research program is also focus on the study the Senescence-Associated Microenvironment (SAM) in tumour suppression. Senescence cells modified the surrounding microenvironment by changing the behaviour and the state of neighbouring inflammatory cells and fibroblasts, and by remodelling of the Extracellular Matrix. We aim to gain insight in such changes and identify a role in non-cell autonomous tumour suppression.

3. Finally, we aim to identify new regulators of OIS by loss of function screens using RNAi technology or drug targeting. To that end we use high content screen platforms like scan^R or ImageExpress micro to perform phenotypic screens based on different markers of senescence.

We expect that these studies may have big implications not only in the understanding of tumour biology itself, but also in several aspects regarding future anticancer strategies because: a) most bio-therapeutics and small drugs targeted secreted factors and its receptors, thus many of the necessary reagents could have already been developed; b) manipulating the senescence secretome to reinforce senescence and activate the immune response for the clearance of targeted cancer cells has been proven efficient in animal models of tumour regression; c) the exploitation of a senescence “bystander” effect mediated by the senescence secretome may facilitate the amplification of anticancer therapies.

The techniques employed by the group include manipulation of primary cells in culture (including retroviral and lentiviral infection), biochemistry, molecular biology and cellular biology. We use gene expression profiling by proteomics or microarray analysis coupled to drug targeted or loss of function RNAi screens to identify putative candidates with activity in OIS. To that purpose, we use state of the art High Content Screen platforms to discover new pathways involved in tumour suppression. Where appropriate, we will try to translate our findings in vitro into animal models of cancer and to validate them in clinical samples (Acosta et al. Cell 2008; Barradas et al. Genes Dev. 2009; Banito et al. Genes Dev. 2009).


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