Year: 2026
Type: preprint
Abstract: To colonize new environments, cancer cells undergo epithelial-to-mesenchymal transition (EMT), enabling detachment and migration, but this phenomenon remains largely controlled by Natural Killer (NK) cells. During EMT, cancer cells shift their metabolism toward fatty acid oxidation (FAO), partly replacing glycolysis to meet the energy demands for migration and invasion. This may impact NK cell-mediated surveillance through an unclear mechanism. Here, we demonstrate that forcing cancer cells to perform FAO by inhibiting pyruvate dehydrogenase kinase 1 with dichloroacetate (DCA) decreases intracellular palmitic and stearic acids, reflecting their utilization as FAO substrates, whereas the rise in neutral lipids reflects compensatory lipid-droplet formation, a hallmark of FAO-driven states linked to EMT. Moreover, DCA activates extracellular signal-regulated kinase-5 (ERK5), triggering EMT and tumor cell migration and invasion. Concomitantly, FAO induces ligands mediating NK cell recognition. NK cells better infiltrated DCA-treated 3D tumor spheroids, where they exerted cytotoxic effects. DCA-treated cells showed increased migration in a zebrafish model, whereas metastasis from mammary cancer cells grafted into immune-deficient mice was enhanced by DCA. Cells undergoing DCA-induced migratory reprogramming exhibit increased susceptibility to NK-cell-mediated control, which limit their invasive potential. Hence, FAO promotes both metastasis and NK-mediated tumor surveillance, highlighting the Achilles’ heel of metastatic cells and therapeutic opportunities. Teaser Metastasis recognition and killing by immune cells, such as NK cells, requires a metabolic shift that relies on lipid metabolism.
Source: Research Square
Authors: Sara Zemiti, Susana Prieto, Steffy Escayg, Benjamin Hay, Amel Bouzid, Catherine Alexia, Carine Jacquard, Noemie Dudzinska, Ananya Sen, Jose Prudenciano, Daouda Abba Moussa, Mauricio Campos Mora, Sabine Gerbal-Chaloin, Michael Constantinides, Alberto Anel, Marion De Toledo, Guillaume Bossis, Ana-Bella Aznar, Daniel Fisher, farida djouad, Yoan Arribat, Jean-François Rossi, Martin Villalba, Delphine Gitenay
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Funders: Bristol-Myers Squibb, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Régional Universitaire de Montpellier, Institut National Du Cancer, Université de Montpellier, Direction Générale de l’offre de Soins, Région Occitanie Pyrénées-Méditerranée
Awards: G1190173965, Next generation metabolomics and fluxomics, from population to single cells, G2450198060, G4291823705, G5802621812, G7080048889, G7240651115, MetaboHUB National Infrastructure of metabolomics and fluxomics, G7376787254, G7740977694, Generation of iChondrocytes to regenerate articular cartilage, G8832936257, Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation
OpenAlex ID: W7204138357