Targeting ELOVL6 to disrupt c-MYC driven lipid metabolism in pancreatic cancer enhances chemosensitivity

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URI: https://hdl.handle.net/10641/7547
ISSN: 2041-1723
DOI: 10.1038/s41467-025-56894-8

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2025-12

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 12% survival rate, highlighting the need for novel therapies. c-MYC overexpression, driven by upstream mutations and amplifications, reprograms tumor metabolism and promotes proliferation, migration and metastasis. This study identifies ELOVL6, a fatty acid elongase regulated by c-MYC, as a potential therapeutic target. Using PDAC mouse models and cell lines, we show that c-MYC directly upregulates ELOVL6 during tumor progression. Genetic or chemical inhibition of ELOVL6 reduces proliferation and migration by altering fatty acid composition, affecting membrane rigidity, permeability and pinocytosis. These changes increase Abraxane uptake and show a synergistic effect when combined with ELOVL6 inhibition in vitro. In vivo, ELOVL6 interference significantly suppresses tumor growth and improves Abraxane response, prolonging survival. These findings position ELOVL6 as a promising target for improving PDAC treatment outcomes.

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Publisher Copyright: © The Author(s) 2025.

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General Chemistry, General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, SDG 3 - Good Health and Well-being, Journal Article, Yes, yes

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García García, A, Ferrer Aporta, M, Vallejo Palma, G, Giráldez Trujillo, A, Castillo-González, R, Calzón Lozano, D, Mora Perdiguero, A, Muñoz Velasco, R, Colina Castro, M, de Simone Benito, E, Torres-Ruiz, R, Rodriguez-Perales, S, Dehairs, J, Swinnen, J V, Garcia-Cañaveras, J C, Lahoz, A, Montalvo Quirós, S, del Pozo-Rojas, C, Luque Rioja, C, Monroy, F, Herráez-Aguilar, D, Alonso Riaño, M, Rodríguez Peralto, J L & Sánchez-Arévalo Lobo, V J 2025, 'Targeting ELOVL6 to disrupt c-MYC driven lipid metabolism in pancreatic cancer enhances chemosensitivity', Nature Communications, vol. 16, no. 1, 1694. https://doi.org/10.1038/s41467-025-56894-8

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