A novel one carbon pathway generates nuclear SAM for chromatin methylation in cancer

Pancreatic Ductal Adenocarcinoma (PDAC) stands as the most common and one of the deadliest forms of pancreatic cancer, largely due to liver metastasis and the lack of effective targeted treatments 1,4. Emerging evidence comparing primary and metastatic cancer lesions suggests that key steps of metastasis are controlled by reversible epigenetic mechanisms, specifically DNA methylation and Histone Post Translational Modifications (PTMs) 10,11. These epigenetic changes are intricately linked to metabolic networks, which supply the essential substrates and cofactors for these modifications, thereby potentially playing a crucial role in metastasis adaptation 12. To explore this interplay between metabolism and epigenetics in PDAC, we leveraged the DepMap database to identify metabolic dependencies in pancreatic cancer cells. Our unbiased analysis revealed Methionine Adenosyltransferase 2A (MAT2A) as a specific vulnerability. MAT2A is a key enzyme in the One Carbon Metabolism (OCM), the pathway for transferring single-carbon units to various substrates. Crucially, the OCM is integral to DNA and histone methylation processes by generating S-adenosylmethionine (SAM), the universal methyl donor whose availability is tightly regulated by MAT2A itself 13. Strikingly, preliminary data reveal a specific nuclear localization of MAT2A in metastatic liver lesions, contrasting with its distribution in primary tumors. Additionally, untargeted metabolomic analysis of human liver metastases revealed that most one-carbon metabolism (OCM) intermediates, including SAM, are downregulated, indicating a high demand for these metabolites in metastatic cells. To mimic these conditions, we developed a Metastasis-like Media (MLM), and our in vitro experiments confirmed that under these conditions, MAT2A translocates to the nucleus, binds to chromatin and is required to sustain histone methyltransferases (HMTs) activity, forming a previously unrecognized OCM nuclear network. Targeting the nuclear activity of MAT2A-including its chromatin binding and interactions with chromatin-associated proteins-could represent a novel therapeutic strategy for metastatic PDAC. Furthermore, this proposal seeks to elucidate the specific mechanisms by which one-carbon metabolism influences DNA and histone methylation patterns, an area that remains unexplored in cancer treatment. Understanding these underlying mechanisms will enable the identification of potential metabolism-targeted therapies to improve the prognosis for PDAC patients. <!--EndFragment-->