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Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance

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  • Alexia Karen Cotte

    (University of Bourgogne-Franche Comté
    Lipids, Nutrition, Cancer
    Cancer and Adaptative Immune Response)

  • Virginie Aires

    (University of Bourgogne-Franche Comté
    Lipids, Nutrition, Cancer
    Cancer and Adaptative Immune Response)

  • Maxime Fredon

    (University of Bourgogne-Franche Comté
    Lipids, Nutrition, Cancer
    Cancer and Adaptative Immune Response)

  • Emeric Limagne

    (Lipids, Nutrition, Cancer
    Cancer and Adaptative Immune Response
    Georges François Leclerc Centre)

  • Valentin Derangère

    (Lipids, Nutrition, Cancer
    Cancer and Adaptative Immune Response
    Georges François Leclerc Centre)

  • Marion Thibaudin

    (University of Bourgogne-Franche Comté
    Lipids, Nutrition, Cancer
    Cancer and Adaptative Immune Response)

  • Etienne Humblin

    (University of Bourgogne-Franche Comté
    Lipids, Nutrition, Cancer
    Cancer and Adaptative Immune Response)

  • Alessandra Scagliarini

    (University of Bourgogne-Franche Comté
    Lipids, Nutrition, Cancer
    Cancer and Adaptative Immune Response)

  • Jean-Paul Pais Barros

    (University of Bourgogne-Franche Comté
    Lipids, Nutrition, Cancer
    Lipidomic Platform)

  • Patrick Hillon

    (University of Bourgogne-Franche Comté
    Lipids, Nutrition, Cancer
    University Hospital)

  • François Ghiringhelli

    (University of Bourgogne-Franche Comté
    Lipids, Nutrition, Cancer
    Cancer and Adaptative Immune Response
    Georges François Leclerc Centre)

  • Dominique Delmas

    (University of Bourgogne-Franche Comté
    Lipids, Nutrition, Cancer
    Cancer and Adaptative Immune Response)

Abstract

Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8+ T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity.

Suggested Citation

  • Alexia Karen Cotte & Virginie Aires & Maxime Fredon & Emeric Limagne & Valentin Derangère & Marion Thibaudin & Etienne Humblin & Alessandra Scagliarini & Jean-Paul Pais Barros & Patrick Hillon & Franç, 2018. "Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02732-5
    DOI: 10.1038/s41467-017-02732-5
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    Cited by:

    1. Yuying Tan & Junjie Li & Guangyuan Zhao & Kai-Chih Huang & Horacio Cardenas & Yinu Wang & Daniela Matei & Ji-Xin Cheng, 2022. "Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Tin-Lok Wong & Jia-Jian Loh & Shixun Lu & Helen H. N. Yan & Hoi Cheong Siu & Ren Xi & Dessy Chan & Max J. F. Kam & Lei Zhou & Man Tong & John A. Copland & Leilei Chen & Jing-Ping Yun & Suet Yi Leung &, 2023. "ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Hyemin Lee & Amber Horbath & Lavanya Kondiparthi & Jitendra Kumar Meena & Guang Lei & Shayani Dasgupta & Xiaoguang Liu & Li Zhuang & Pranavi Koppula & Mi Li & Iqbal Mahmud & Bo Wei & Philip L. Lorenzi, 2024. "Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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