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 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.
Authors
- Ana García García (ORCID: https://orcid.org/0000-0001-7875-4943)
- Raquel Castillo‐González (ORCID: https://orcid.org/0000-0002-9877-2126)
- Jonas Dehairs (ORCID: https://orcid.org/0000-0002-6789-2264)
- Johannes V. Swinnen (ORCID: https://orcid.org/0000-0002-7720-5077)
- Sandra Montalvo-Quirós (ORCID: https://orcid.org/0000-0002-5031-6455)
- Víctor J. Sánchez‐Arévalo Lobo (ORCID: https://orcid.org/0000-0002-4561-1505)
- Marina Alonso (ORCID: https://orcid.org/0000-0003-1293-1075)
- Juan Carlos García‐Cañaveras (ORCID: https://orcid.org/0000-0001-7112-1537)
- Raúl Torres (ORCID: https://orcid.org/0000-0001-9606-0398)
- Elena de Simone Benito (ORCID: https://orcid.org/0009-0003-3119-4370)
- Raúl Muñoz Velasco (ORCID: https://orcid.org/0000-0003-0621-167X)
- Sandra Rodríguez (ORCID: https://orcid.org/0000-0001-7221-3636)
- Francisco Monroy (ORCID: https://orcid.org/0000-0001-6455-3083)
- Ángela Maria Trujillo (ORCID: https://orcid.org/0009-0007-7259-2286)
- Agustín Lahoz (ORCID: https://orcid.org/0000-0001-7232-0626)
- José Luis Rodríguez‐Peralto (ORCID: https://orcid.org/0000-0002-6578-7153)
- Diego Herráez‐Aguilar (ORCID: https://orcid.org/0000-0002-9764-4210)
- Germán Vallejo-Palma (ORCID: https://orcid.org/0009-0001-0770-0355)
- M.A. González Castro (ORCID: https://orcid.org/0009-0002-3655-8260)
- Carlos Rotellar Rioja (ORCID: https://orcid.org/0009-0009-9112-2284)
- David Calzón Lozano (ORCID: https://orcid.org/0009-0003-3480-9908)
- Carlos del Pozo-Rojas (ORCID: https://orcid.org/0009-0003-8128-4438)
- María Ferrer Aporta (ORCID: https://orcid.org/0000-0003-4349-1797)
- Alberto Mora Perdiguero (ORCID: https://orcid.org/0000-0001-6306-5467)
Institutions
- Universidad Complutense de Madrid (ES)
- Universidad Francisco de Vitoria (ES)
- Research Institute Hospital 12 de Octubre (ES)
- Spanish National Cancer Research Centre (ES)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Hospital Universitario 12 De Octubre (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Centro de Investigación Biomédica en Red (ES)
- Leitat Technological Center (ES)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (ES)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-16
- DOI
- https://doi.org/10.1038/s41467-025-56894-8
- Citations
- 12
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 11.23
Funders
- Universidad Francisco de Vitoria
- Instituto de Salud Carlos III