​Targeting Palmitic Acid Signaling Machinery to Inhibit Metastatic Cancer

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Despite recent breakthroughs in immunotherapy and cancer research, metastasis continues to be responsible for 90% of cancer related deaths. While surgical resection and adjuvant therapy can cure localized tumors, once tumor cells metastasize, cancer remains largely incurable. Increasing evidence indicates that lipids play a crucial role in the metastatic process by providing energy and membrane components required for cell migration and outgrowth, and also by triggering specific signaling cascades that prime cancer cells into a metastatic program (Martin-Perez et al., Cell Metabolism 2022). Importantly, we have found that palmitic acid, but not other fatty acids, promotes metastasis in a large number of tumors, and that metastatic initiating cells require a lipid metabolism reprogramming driven by an epigenetic remodeling (Pascual et al. Nature 2017; Pascual et al. Nature 2021). We have solid evidence that fatty acids not only promote metastasis by providing energy to metastatic cells (Delauney et al. Nature 2022), but also by specifically modulating protein lipidation. Thus, targeting this particular lipid signaling machinery may represent an unexplored solution to combat metastasis. PalmitoMET aims to identify novel molecules capable of inhibiting specific protein lipidation to treat metastasis in preclinical models, with the aim to bring them closer to the clinic. Inhibitors found during this project have the potential to become first-in-class drugs, making this project a high risk but high gain project, considering the very large and growing market we are addressing