LDLR-mediated lipidome-transcriptome reprogramming in cisplatin insensitivity.

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Platinum-based chemotherapy is crucial for cancer treatment but faces variable efficacy.
• The role of lipoprotein receptors, like the low-density lipoprotein receptor (LDLR), in cancer development is recognized, but their impact on chemotherapy sensitivity remains unclear.
• Epithelial ovarian cancer (EOC) presents a suitable model to investigate the LDLR's role in chemoresistance.

Purpose of the Study:

• To elucidate the mechanism by which the low-density lipoprotein receptor (LDLR) affects sensitivity to platinum-based chemotherapy in epithelial ovarian cancer (EOC).
• To identify potential biomarkers for predicting chemotherapy response in EOC patients.

Main Methods:

• Analysis of public cDNA microarray data and a single cohort study to correlate LDLR expression with EOC patient prognosis.
• In vitro and in vivo experiments involving the manipulation (overexpression and knockdown) of LDLR in EOC cells to assess cisplatin sensitivity.
• Trans-omics approaches to map the regulatory axis involving LDLR, lipidome, and transcriptome.

Main Results:

• LDLR expression was positively associated with better disease prognosis in EOC patients undergoing platinum-based chemotherapy.
• Knockdown of LDLR sensitized EOC cells to cisplatin, while LDLR overexpression led to insensitivity.
• A regulatory axis (LDLR→Lyso-phosphatidylcholine (LPC)→FAM83B→FGFRs) was identified, linking lipid metabolism and gene expression to cisplatin sensitivity.

Conclusions:

• The LDLR plays a significant role in regulating platinum chemotherapy sensitivity in epithelial ovarian cancer.
• The identified LDLR→LPC→FAM83B→FGFRs axis represents a novel mechanism of tumor macroenvironmental regulation of therapy outcomes.
• LDLR expression can potentially serve as a predictive biomarker for chemotherapy sensitivity in EOC.