Senescence is a cellular program characterized by a stable cell cycle arrest and a specific secretory phenotype, with an essential impact in diverse physiological and pathological settings. Senescence can act as a stress response triggered by different forms of cellular damage such as genotoxic stress, oncogene activation or mitochondrial dysfunction, among others. In addition to this role against stress, senescence also participates in the control of cell balance and tissue homeostasis in the context of normal physiology and embryonic development.
Reflecting the importance of senescence for normal organismal function, a growing list of pathologies, many of them age-related, have been associated to senescence dysfunction. These include cancer, atherosclerosis, fibrosis or diabetes among others. Strikingly, the role of senescence in disease is highly context dependent, with examples of both protective and pathogenic effects. In the context of cancer, senescence can display a dual role. On one hand, it acts as an effective tumor suppressor barrier that prevents tumor initiation, by blocking the proliferation of cells with potentially oncogenic alterations. Conversely, the accumulation of senescent cells in tumors, due to therapeutical interventions or other factors is usually detrimental, being associated to increased tumor growth, aggressiveness and dissemination.
In our lab, we are interested in understanding the basic mechanisms that control cell senescence, its crosstalk with other essential cell processes, and how the disruption of the physiological program of senescence may contribute to cancer and other diseases. To address these questions, we use a combination of experimental approaches that include cell biology, transcriptomics and mouse models to pursue the following lines of research.
Senescence and plasticity.
Recent evidence has revealed a complex link between senescence and cell plasticity in different settings. In this context, work from our lab and others have shown the differential expression of lineage-specific genes in cellular models of senescence, some of which are aberrantly expressed in tumors. We have also recently shown the impact of the senescence program in the specification of the myofibroblastic phenotype in a process involving the senescent secretome or SASP. With this background, we are currently investigating the functional link between senescence and cell plasticity in cancer and other pathological and physiological settings, with a special focus on the role of the senescence secretome in this process.
Senescence in cancer and development.
We have recently shown that the homeoprotein SIX1 is an essential repressor of senescence in different cellular settings. SIX1 is a member of the SIX/EYA functional pathway, with essential roles in organogenesis, and alterations in this pathway are linked to the human BOR (Branchio-Oto-Renal) developmental syndrome. On the other hand, SIX1 is an oncogene, frequently activated in different types of tumors, where it is usually associated to poor prognosis, stem phenotypes and invasiveness. Based on the well-established role of senescence in both embryogenesis and tumorigenesis, we are currently exploring the relevance of senescence in pathological situations linked to SIX1 dysfunction both in the context of cancer and embryonic development.