Lysophosphatidylcholine Acyltransferase 2-mediated Lipid Droplet Production Supports Colorectal Cancer Chemoresistance

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Jan 24

PMID 29358673

Citations 157

Authors

Alexia Karen Cotte

Virginie Aires

Maxime Fredon

Emeric Limagne

Valentin Derangere

Marion Thibaudin

Etienne Humblin

Alessandra Scagliarini

Jean-Paul Pais de Barros

Patrick Hillon

Francois Ghiringhelli

Dominique Delmas

Affiliations

Soon will be listed here.

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.

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