Periodic Reporting for period 4 - EPICAMENTE (At the epigenetics-cancer metabolism interface)
Berichtszeitraum: 2024-05-01 bis 2025-10-31
Cancer remains a major societal challenge due to its capacity to adapt, evolve, and develop resistance to therapy. Despite significant advances, no current treatment guarantees complete eradication or prevents relapse, largely because most therapies target single pathways while cancer cells exploit multiple interconnected mechanisms to survive. This highlights a critical unmet need: identifying new vulnerabilities that can be targeted through combinatorial therapeutic strategies.
Historically, metabolism and chromatin regulation have been studied as separate domains. Metabolic processes were considered confined to the cytoplasm and mitochondria, while the nucleus was viewed as the site of genome regulation. EPICAMENTE addressed this conceptual gap by investigating whether metabolism directly operates on chromatin to control gene expression and cancer cell behaviour.
The overall objective of EPICAMENTE was to define the interplay between cancer metabolism and epigenetic regulation by systematically characterising metabolic enzymes associated with chromatin and determining their functional role in genome regulation and tumour progression. A key goal was to establish whether this chromatin–metabolism crosstalk represents a fundamental and targetable vulnerability in cancer, with potential to inform new combinatorial therapeutic strategies.
Historically, metabolism and chromatin regulation have been studied as separate domains. Metabolic processes were considered confined to the cytoplasm and mitochondria, while the nucleus was viewed as the site of genome regulation. EPICAMENTE addressed this conceptual gap by investigating whether metabolism directly operates on chromatin to control gene expression and cancer cell behaviour.
The overall objective of EPICAMENTE was to define the interplay between cancer metabolism and epigenetic regulation by systematically characterising metabolic enzymes associated with chromatin and determining their functional role in genome regulation and tumour progression. A key goal was to establish whether this chromatin–metabolism crosstalk represents a fundamental and targetable vulnerability in cancer, with potential to inform new combinatorial therapeutic strategies.
Over the course of the project, EPICAMENTE combined chromatin proteomics, quantitative mass spectrometry, metabolomics, imaging, and functional genomics to systematically investigate nuclear metabolism.
A major achievement of the project was the generation of the first comprehensive chromatome-scale analyses across human tissues and cancer models, revealing that hundreds of metabolic enzymes localise to chromatin in a context-dependent manner . This finding transformed the understanding of nuclear metabolism from an isolated phenomenon into a widespread and organised feature of genome biology.
Beyond mapping, the project provided mechanistic evidence that chromatin-associated metabolic enzymes actively regulate key nuclear processes, including transcriptional control, DNA repair, genome stability, and cell cycle progression. Several studies demonstrated that local metabolic activities on chromatin sustain epigenetic states and gene expression programs essential for cancer cell proliferation.
Importantly, EPICAMENTE showed that the spatial redistribution of metabolic enzymes can create specific cellular vulnerabilities and modulate therapeutic response independently of genetic background. These findings establish nuclear metabolism as a novel axis for cancer stratification and intervention.
The project also delivered significant technological innovation, including chromatome profiling workflows and proteoform-resolved mass spectrometry approaches, enabling systematic and reproducible analysis of chromatin-associated metabolism. These tools, together with the datasets generated, have been disseminated through high-impact publications, open-access resources, and international collaborations, ensuring broad uptake by the scientific community.
In terms of exploitation, the discoveries have led to the identification of clinically relevant metabolic vulnerabilities and supported the development of intellectual property and translational strategies aimed at improving cancer treatment.
A major achievement of the project was the generation of the first comprehensive chromatome-scale analyses across human tissues and cancer models, revealing that hundreds of metabolic enzymes localise to chromatin in a context-dependent manner . This finding transformed the understanding of nuclear metabolism from an isolated phenomenon into a widespread and organised feature of genome biology.
Beyond mapping, the project provided mechanistic evidence that chromatin-associated metabolic enzymes actively regulate key nuclear processes, including transcriptional control, DNA repair, genome stability, and cell cycle progression. Several studies demonstrated that local metabolic activities on chromatin sustain epigenetic states and gene expression programs essential for cancer cell proliferation.
Importantly, EPICAMENTE showed that the spatial redistribution of metabolic enzymes can create specific cellular vulnerabilities and modulate therapeutic response independently of genetic background. These findings establish nuclear metabolism as a novel axis for cancer stratification and intervention.
The project also delivered significant technological innovation, including chromatome profiling workflows and proteoform-resolved mass spectrometry approaches, enabling systematic and reproducible analysis of chromatin-associated metabolism. These tools, together with the datasets generated, have been disseminated through high-impact publications, open-access resources, and international collaborations, ensuring broad uptake by the scientific community.
In terms of exploitation, the discoveries have led to the identification of clinically relevant metabolic vulnerabilities and supported the development of intellectual property and translational strategies aimed at improving cancer treatment.
EPICAMENTE has advanced the field beyond the state of the art by redefining metabolism as a spatially organised and functional component of chromatin biology. Prior to this work, the presence of metabolic enzymes in the nucleus was considered anecdotal; this project established it as a general and biologically significant principle.
By demonstrating that metabolic enzymes directly operate on chromatin to regulate genome function, EPICAMENTE has introduced a new conceptual framework in which metabolism, epigenetics, and gene regulation are functionally integrated. This represents a paradigm shift in both cancer biology and cell biology more broadly.
The project has also laid the foundation for a new field centred on nuclear metabolism and spatial metabolic regulation. The methodologies and datasets generated enable future studies to systematically identify nuclear-specific metabolic dependencies across diseases and physiological contexts.
Overall, EPICAMENTE delivers both conceptual and translational impact. It opens new avenues for the development of combinatorial therapies targeting nuclear metabolic vulnerabilities, with the potential to overcome resistance mechanisms and improve patient outcomes. At the same time, it establishes a long-term research direction with broad implications for development, ageing, and disease.
By demonstrating that metabolic enzymes directly operate on chromatin to regulate genome function, EPICAMENTE has introduced a new conceptual framework in which metabolism, epigenetics, and gene regulation are functionally integrated. This represents a paradigm shift in both cancer biology and cell biology more broadly.
The project has also laid the foundation for a new field centred on nuclear metabolism and spatial metabolic regulation. The methodologies and datasets generated enable future studies to systematically identify nuclear-specific metabolic dependencies across diseases and physiological contexts.
Overall, EPICAMENTE delivers both conceptual and translational impact. It opens new avenues for the development of combinatorial therapies targeting nuclear metabolic vulnerabilities, with the potential to overcome resistance mechanisms and improve patient outcomes. At the same time, it establishes a long-term research direction with broad implications for development, ageing, and disease.