Periodic Reporting for period 3 - EPICAMENTE (At the epigenetics-cancer metabolism interface)
Reporting period: 2022-11-01 to 2024-04-30
Best ideas with an interdisciplinary nature and in emerging fields of research must be supported with the purpose to generate novel knowledge that might be translated into potential applications for the benefit of people and economic growth. In this regard, my ERC project is very timely, highly interdisciplinary and innovative and has a high translational potential. Finding novel strategies to treat cancer patients is an increasing challenge given the fact that there is no therapy at the moment that can guaranty a complete eradication or no-risk of relapse. The ability of cancer to evolve and become resistance to anticancer treatment teaches us that we must use combinatorial treatments to have an enhanced anticancer response. Indeed, even the most innovative immunotherapy strategies fail if not given in combination with chemotherapy. Attacking multiple essential aspects of the cancer cell can be therefore crucial to control or block tumor proliferation. For this reason, I decided to focus my research in this novel aspect of cancer biology: chromatin metabolism.With EPICAMENTE, we aim at dissecting the epigenetic scenario orchestrated by chromatin-bound metabolic enzymes associated with cancer metabolism rewiring. The systematic identification of cross-talk between epigenetic regulation and cancer metabolism will redefine the current concept of cancer biology, describing a new and fluid scenario in which metabolic enzymes can functionally regulate epigenetics, gene expression and cancer cell proliferation by localising on chromatin. We hypothesise that the chromatin localisation of metabolic enzymes does not exclusively happen in cancer but also in other pathological and physiological situations (e.g. different diseases or specification of cell identity). For this reason, the technological developments and resources generated during the course of this project will be made available with open access publications and online accessible datasets, as it is expected that the scientific community will greatly benefit from them.
Experiments are flowing smoothly, and we could, despite the pandemic, generate most of the tools required for the developing of the project. We have been able to finish the chromatin extraction of multiple cell lines required for the realization of Aim1 and we are performing omics experiments (transcriptomics, proteomics, reporter-based functional genomics) for selected metabolic enzymes detected on chromatin in particular types or subtypes of cancer. This set of omics experiments will allow us to identify the mode of action of selected metabolic enzymes on chromatin in specific cancer types or subtypes, with the aim of targeting enzyme localization as a future anticancer therapeutic strategy. Regarding this, we established a collaboration to chemically induce the degradation of metabolic enzymes in the nuclear compartment via PROTACS, to complement the genetic approach described in the Epicamente project.
This project will certainly set the basis for further developments. For example, proving that the local accumulation of metabolites can guide precise chromatin architectures and regulate transcription can resolve the molecular mechanism of recent evidences that gene expression and heterochromatin formation are controlled by liquid-liquid phase separation. The local concentration of metabolites may be the trigger of liquid-liquid phase separation, by promoting a membrane-free delimitation of selective areas of the chromatin environment (e.g. super enhancers, promoters or heterochromatin regions) whose structure is essential for the binding or exclusion of the transcription machinery. Future investigation of this possibility will further increase our understanding of the molecular interactions regulating cancer development and progression, which will result in the generation of scientific knowledge that might open up better opportunities for cancer therapy. In addition, the identification of direct links between metabolism and epigenetics will foster the investigation of similar scenarios in other biological contexts, either physiological (eg: development) or pathological (other non-cancer deseases).