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

Alexia Karen Cotte,Alessandra Scagliarini,Valentin Derangère,Dominique Delmas,François Ghiringhelli,Virginie Aires,Marion Thibaudin,Emeric Limagne,Maxime Fredon,Etienne Humblin,Patrick Hillon,Jean-Paul Pais De Barros

doi:10.1038/s41467-017-02732-5

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.

Highlights

Lipid droplet (LD) accumulation is a well-recognised hallmark of cancer
In the Lands cycle, LPCAT are the key enzymes connecting Lands and Kennedy pathways because they allow re-acylation of LPC at the sn-2 position to yield PC9,10. We found that both Kennedy and Lands cycle enzymes were differentially expressed across colorectal cancer (CRC) cell lines (Supplementary Fig. 2a, b); only lysophosphatidylcholine acyltransferase 2 (LPCAT2) expression was positively and significantly (Spearman’s correlation p value = 0.0167) correlated with basal LD content (Fig. 1b, c; Supplementary Fig. 2a, b)
Despite an increasing number of reports highlighting the role of LD accumulation in tumour progression and cancer aggressiveness[5,7,16], few studies have investigated the role of these intracellular lipid bodies in tumour resistance to chemotherapy, which is a major obstacle for treatment success in cancer patients

Summary

Introduction

Lipid droplet (LD) accumulation is a well-recognised hallmark of cancer. the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under chemotherapeutic conditions. Besides the Warburg effect, tumour cells undergo lipid remodelling mostly characterised by aberrant de novo lipogenesis, cholesterogenesis due to oncogenic-driven lipogenic enzyme overexpression (e.g., fatty-acid synthase (FASN), 3-hydroxy-3methylglutaryl-CoA reductase (HMGCR)) This bulk of newly synthesised lipids serves for membrane biogenesis and synthesis of essential lipid-derived second messengers (e.g., phosphatidic acid, phosphoinositides, eicosanoids, including prostaglandin E2 (PGE2)) to maintain cancer cell proliferation and survival[1,2,3]. The remodelling of PC species occurs with the re-acylation of lysophosphatidylcholine (LPC) by the enzymes of the Lands cycle: lysophosphatidylcholine acyltransferase LPCAT1 and LPCAT2 isoforms participating in LD expansion and stability[11] These organelles have been shown to promote proliferation[12] or survival under nutrient stress[13,14], to reduce intracellular lipotoxicity[15]. We show that LPCAT2 overexpression and LD overproduction confer CRC cell chemoresistance by blocking chemotherapy-induced ER stress, calreticulin (CRT) membrane translocation and subsequent immunogenic cell death (ICD)

Methods

Results

Conclusion