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

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 identifi...

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Authors: García García, Ana, Ferrer Aporta, María, Vallejo Palma, Germán, Giráldez Trujillo, Antonio, Castillo-González, Raquel, Calzón Lozano, David, Mora Perdiguero, Alberto, Muñoz Velasco, Raúl, Colina Castro, Miguel, de Simone Benito, Elena, Torres-Ruiz, Raúl, Rodriguez-Perales, Sandra, Dehairs, Jonas, Swinnen, Johannes V., Garcia-Cañaveras, Juan Carlos, Lahoz, Agustín, Montalvo Quirós, Sandra, del Pozo-Rojas, Carlos, Luque Rioja, Clara, Monroy, Francisco, Herráez-Aguilar, Diego, Alonso Riaño, Marina, Rodríguez Peralto, José Luis, Sánchez-Arévalo Lobo, Víctor Javier
Format: article
Publication Date:2025
Country:España
Institution:Universidad Francisco de Vitoria
Repository:DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria
Language:English
OAI Identifier:oai:ddfv.ufv.es:10641/6809
Online Access:https://hdl.handle.net/10641/6809
Access Level:Open access
Keyword:General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy
SDG 3 - Good Health and Well-being
Journal Article
yes
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Summary: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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