Plain language summary
Lipid droplet (LD) accumulation has been observed in an increasing number of cancer cell lines and is now a well-recognised hallmark of cancer. While the significance of LD accumulation remains unclear, recent studies have suggested it plays a role in tumour cell chemoresistance mechanisms. This study aims to fill in the gaps in the literature regarding LD formation and function under chemotherapy conditions in colorectal cancer cell models. For the first time, this study demonstrates a pertinent mechanism linking LD accumulation and resistance to conventional chemotherapies. The authors found that LD production is driven by the enzyme lysophosphatidylcholine acyltransferase 2 (LPCAT2), and that chemotherapy can trigger LD production, promoting chemoresistance. The authors conclude these findings could be useful for both prognostic factors as well as predictive factors for the patient’s responsiveness to conventional therapies.
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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