The Landeira lab is driven by the belief that human health is not genetically predetermined. We hypothesize that the onset of aging-associated diseases is mostly a consequence of the deterioration of the epigenetic memory that eventually leads to changes in cell identity and the onset of aging-associated diseases including cancer. We aim to contribute to establish the molecular foundation of epigenetic memory, identify which are the key epigenetic pathways that drive aging and cancer progression, and contribute to the design of new therapies that reverse aging-associated diseases using epigenetic drugs. We are currently developing three research lines in the lab:

What is the molecular foundation of epigenetic memory?

Revealing the key molecular pathways that facilitate the formation of complex multicellular organisms like humans is a exciting task. Upon fusion of the sperm and oocyte cells, a single cell named the zygote is formed. During organism development the zygote goes through a vast number of proliferation and differentiation rounds that generate over 10¹² cells that are genetically identical but functionally distinct, and that organise to produce 78 organs that compose the adult human body. Cell specialization depends on the establishment of distinct epigenetic configurations that facilitate the expression of set of cell-type-specific genes. Importantly, cell-type-specific epigenetic patterns need to be “memorized” and maintained for a lifetime, because the original differentiation signal instructing the change in gene expression during development is no longer present during the adult life. Importantly, many types of environmental stimulus can perturb our epigenetic memory, and thus we hypothesize that many diseases associated to aging are a consequence of the perturbation of the original epigenetic configuration that was laid on the genome during development. Because you cannot fix what you don’t know, in our lab we want to dissect the mechanism by which epigenetic regulators promote the perpetuation of epigenetic memory. To this end, we study the molecular details as to how two hallmark epigenetic systems (Polycomb proteins and H3K9 methyltransferases) enable the perpetuation of epigenetic memory in mouse pluripotent stem cells. Our recent findings ^1,2 suggest that cellular memory is supported by an epigenetic cycle in which reversible activities carried out by epigenetic regulators in coordination with cell cycle transition create a multiphasic system that can accommodate both maintenance of cell identity and cell differentiation in proliferating stem cell populations ³.

Is the loss of epigenetic information the reason we age? Can we slow down the pace of aging by stabilizing our epigenome?

Deciphering the molecular basis of human aging is an exciting challenge in fundamental biology with great implications in public health. Emerging reports suggest that aging can be induced by environmental factors that challenge the stability of epigenetic information stored on our genomes. We support the idea that the aging process is driven by the progressive loss of youthful epigenetic information laid during development, the retrieval of which via epigenetic reprogramming can improve the function of damaged and aged tissues by catalysing age reversal ⁴. Using pluripotent cells and mutant mice as model systems, we are currently investigating which are the epigenetic factors that build our young epigenome, and that protects us from aging during our lifespan. We envision that identification of such mechanisms together with a better understanding of the molecular basis of epigenetic memory will allow us to devise safe pharmacological interventions that protect us from the loss of youth-encoding epigenetic memory during our lifespan.  

Is epigenetic instability a driver of cancer progression? Can we cure cancer by modulating the cancer epigenome?

Metastasis is the cause of ~90% of cancer-associated mortality and therefore, to cure cancer, it is urgent to develop new therapies that block the capacity of cancer cells to disseminate throughout the human body. Metastatic dissemination relies on the continuous positive selection of cancer cells that are functionally optimized to survive in the different physiological and pharmacological environments occurring during disease progression. In our lab, we believe that functional cell-to-cell heterogeneity required for cancer progression relies, not only on different combination of genetic mutations accumulated in their genome, but also on distinct epigenetic configurations that dictate the behaviour of individual cells ⁵. We use cancer cells derived from human patients and mouse xenotransplant models to investigate how epigenetic memory affects cancer progression, with the aim to contribute to the development of new therapies that block disease progression by targeting epigenetic regulators. We have recently demonstrated that the epigenetic proteins Polycomb enable the residence of cancer cells in a metastable state that facilitate shifts within the epithelial and mesenchymal spectrum, enabling metastatic dissemination ^6,7. These findings provide key information for effective application of currently available Polycomb inhibitors in human cancer patients.

Selected bibliography