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<p>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 <i>ELOVL6</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月16日

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  • Ana García García,
  • María Ferrer Aporta,
  • Germán Vallejo Palma,
  • Antonio Giráldez Trujillo,
  • Raquel Castillo-González,
  • David Calzón Lozano,
  • Alberto Mora Perdiguero,
  • Raúl Muñoz Velasco,
  • Miguel Colina Castro,
  • Elena de Simone Benito,
  • Raúl Torres-Ruiz,
  • Sandra Rodriguez-Perales,
  • Jonas Dehairs,
  • Johannes V. Swinnen,
  • Juan Carlos Garcia-Cañaveras,
  • Agustín Lahoz,
  • Sandra Montalvo Quirós,
  • Carlos del Pozo-Rojas,
  • Clara Luque Rioja,
  • Francisco Monroy,
  • Diego Herráez-Aguilar,
  • Marina Alonso Riaño,
  • José Luis Rodríguez Peralto,
  • Víctor Javier Sánchez-Arévalo Lobo

摘要

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.