Cell senescence, cancer and aging (ColladoLab)
When cells are confronted by aggressions that compromise the integrity of the genome in an unrepairable manner, they can undergo apoptosis and disappear, or they can impose a permanent and stable cell cycle arrest known as cellular senescence to avoid the emergence of clones of cells with corrupted genetic information. Senescent cells then start signaling by secreting a plethora of factors that will promote dedifferentiation, proliferation, matrix remodeling, immune system activation, with the aim of repairing the tissue. Thus, cellular senescence is involved in tissue remodeling during embryo development, tissue repair, and regeneration. Apart from this basic tissue homeostasis activity, senescence protects us from cancer development by restricting the proliferation of cells carrying activated oncogenes.
These senescent damaged cells are recognized by the immune system and are cleared out once the tissue has been repaired. However, as we age, senescent cells tend to accumulate in tissues, promoting chronic inflammation and fibrosis, resulting in tissue dysfunction that can even lead to neoplastic transformation.
One particular setting in which senescence plays a dual role is cancer therapy. Cancer cells usually die after treatment with chemo or radiotherapy but if not, they can enter this state of cell senescence, restricting the effectiveness of the therapy and altering the tumor microenvironment in a manner that can be tumor promoting and enhancing malignancy.
Líneas de investigación
In recent years, it has been possible to prove that removing senescent cells as they are produced, and once they have performed their role, to avoid their accumulation provides a health benefit related with delaying and even improving age-related diseases. Apart from experimental mouse models, it has been possible to identify compounds with senescent cell specific cytotoxicity, known as senolytics. These senolytic compounds offer a great promise for the treatment and/or prevention of aging and its associated diseases.
In our lab, we have identified a new class of these compounds, the Cardiac Glycosides, mainly in the context of a combined chemotherapy of cancer, to try to clear out senescent cancer cells arising after conventional treatments. This is what has become known as a “one-two punch” strategy against cancer, combining senescence-inducing chemo or radiotherapy with senolytic compounds. This strategy provides a more robust and definitive therapy with less toxic secondary effects.
- Continuing with this idea, we have screened a library of more than 100k compounds and identified some very interesting compounds showing senolytic activity. We now need to validate them, find their targets in cells and try to develop them into lead compounds that could potentially result in new drugs.
- The lack of specific biomarkers to detect senescent cancer cells after patient treatment is restricting the application of all our knowledge in the field of senescence to cancer therapy. For this reason, one of our main objectives in the lab is to identify specific markers produced by cancer cells after therapy only when these cells respond to the therapy by entering senescence.
- We are convinced that we will find a way to leverage our knowledge of cell senescence to improve cancer treatment. One path will be to identify mechanisms of cancer cell resistance related with the process of cell senescence. This is something we have already started to study and that is leading us to describe new mechanisms of resistance to cancer therapy.
- One of our favorite tools in the lab along the years is cellular reprogramming. After using it to better understand cell plasticity during cancer, we are now using it in a high fat diet-induced obesity or in cell senescence. These are exciting projects that offer the promise of intriguing results.
Miembros
Publicaciones seleccionadas
The role of cellular senescence in tissue repair and regeneration
Developmentally-programmed cellular senescence is conserved and widespread in zebrafish
Identification and characterization of Cardiac Glycosides as senolytic compounds
Adult Sox2+stem cell exhaustion in mice results in cellular senescence and premature aging