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

Alexia Karen Cotte (), Virginie Aires, Maxime Fredon, Emeric Limagne, Valentin Derangère, Marion Thibaudin, Etienne Humblin, Alessandra Scagliarini, Jean-Paul Pais Barros, Patrick Hillon, François Ghiringhelli and Dominique Delmas ()
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Alexia Karen Cotte: University of Bourgogne-Franche Comté
Virginie Aires: University of Bourgogne-Franche Comté
Maxime Fredon: University of Bourgogne-Franche Comté
Emeric Limagne: Lipids, Nutrition, Cancer
Valentin Derangère: Lipids, Nutrition, Cancer
Marion Thibaudin: University of Bourgogne-Franche Comté
Etienne Humblin: University of Bourgogne-Franche Comté
Alessandra Scagliarini: University of Bourgogne-Franche Comté
Jean-Paul Pais Barros: University of Bourgogne-Franche Comté
Patrick Hillon: University of Bourgogne-Franche Comté
François Ghiringhelli: University of Bourgogne-Franche Comté
Dominique Delmas: University of Bourgogne-Franche Comté

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02732-5

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