Multiomics analysis of cancer chemotherapy sensitivity
Research Article
LDLR expression influences ovarian cancer cells’ sensitivity to platinum-based chemotherapy.
About the authors
Nuala Del Piccolo, Olga (Olya) Vvedenskaya
Nuala Del Piccolo
Science Writer
Dr. Nuala Del Piccolo did her PhD in materials sciences at Johns Hopkins. She is passionate about communicating science to a wide audience.
Olga (Olya) Vvedenskaya
Sci. Communications Officer
Dr. Dr. Olya Vvedenskaya studied medicine, and further obtained her PhD in the field of molecular oncology. She loves to deliver scientific messages in a clear and accessible manner.
• Ovarian cancer response to chemotherapy varies • The receptor LDLR may be involved in cancer development, progression, and therapy response • Multiomics found a link between LDLR and chemosensitivity
Dr. Nuala Del Piccolo did her PhD in materials sciences at Johns Hopkins. She is passionate about communicating science to a wide audience.
Olga (Olya) Vvedenskaya
Sci. Communications Officer
Dr. Dr. Olya Vvedenskaya studied medicine, and further obtained her PhD in the field of molecular oncology. She loves to deliver scientific messages in a clear and accessible manner.
OVARIAN cancer is among the most common cancers worldwide, with over 300 000 women being diagnosed with ovarian cancer every year. Like other solid tumors, ovarian cancer is frequently treated with platinum-based chemotherapies such as cisplatin.
Tumor responses to platinum-based therapies may vary due to multiple factors, some of them could include lipid metabolism specifics, hypoxia, and genetic variability. Cancer cells often reprogram lipid pathways to support rapid growth, influencing drug uptake and resistance. Hypoxic tumor microenvironments contribute to treatment resistance by altering survival pathways and reducing drug penetration. Additionally, genetic mutations may modulate therapy response. Understanding these interconnected factors can help develop more targeted and effective treatment strategies, enhancing the efficacy of platinum-based therapies.
Ovarian cancers can be classified into four subtypes – serous, mucinous, endometrioid, and clear-cell – based on their histology. These ovarian cancer subtypes exhibit varying sensitivity to platinum-based chemotherapy and seem to incorporate different amounts of lipids into their cells. Since lipid homeostasis has previously been linked to cancer progression – for example, of breast cancer – scientists hypothesized that the lipid profile of ovarian cancer cells may be associated with chemo-sensitivity.
Published in Endocrine-Related Cancer, a team of researchers at China Medical University Hospital explored the relationships between low-density lipoprotein receptor (LDLR), ovarian cancer subtypes, lipid metabolism, and sensitivity to platinum-based chemotherapy. The results of this study indicate that LDLR expression influences chemo-sensitivity.
The four ovarian cancer subtypes were modelled using cell lines, murine models, fixed patient tissue samples, and data from The Cancer Genome Atlas. Viability, chemosensitivity, lipidome, and transcriptome profiles of these models were characterized.
LDLR is a cell surface receptor responsible for transporting low-density lipoproteins – the particles that traffic cholesterol through the bloodstream – into the cell. In both ovarian cancer cell lines and patient samples, LDLR expression was high in endometrioid and clear-cell and low in serous and mucinous ovarian cancers.
LDLR expression in ovarian cancer subtypes:A Immunohistochemistry staining of LDLR. B Quantitation of Immunohistochemistry (IHC) scores of LDLR. The patient numbers are serous (n = 16), mucinous (n = 29), endometrioid (n = 50), and clear-cell (n = 20). ‘Strong’ indicates an IHC score of 3 or above; ‘weak’ indicates an IHC score lower than 3. Chang et al., ERC (2020), 10.1530/ERC-19-0095
Additionally, in an in vitro assay, serous cells were more sensitive than clear-cell and endometrioid cells to cisplatin. Consistent with this observation, increasing LDLR expression in serous cells and knocking down expression in clear-cell and endometrioid cells respectively reduced and enhanced chemo-sensitivity.
In search of a mechanistic explanation for the relationship between LDLR expression and chemo-sensitivity, cell lines representing the four ovarian cancer subtypes were characterized via lipidomics technology. The results revealed distinct lipid profiles in each cell line, including high expression of ether phospholipids in serous and endometrioid cells; and glycerol esters in clear-cell and endometrioid cells.
Lipidome profiling of ovarian cancer subtypes: Heatmap lipid profiles of serous (SKOV3, OVCAR3), endometrioid (MDAH-2774, TOV-112D), and clear-cell (ES2, TOV-21G) ovarian cancer cell lines. The color spectrum indicates the variation of lipid species. Chang et al., ERC (2020), 10.1530/ERC-19-0095
Next, control and LDLR knockdown clear-cell and endometrioid cells were characterized via lipidomic and transcriptomic assays. Multiomics analysis of these data showed that LDLR knockdown led to an increase of the lyso-phosphatidylcholine lipid class, and a decrease of the ether-linked phosphatidylethanolamine lipid class, and altered the expression of 1404 genes.
Lipid classes change in LDLR knockdown cells. Statistically significan increase in LPC abundance and decrease in PE O- abundance was measured.
Chang et al., ERC (2020), 10.1530/ERC-19-0095
Subsequent experiments and analysis identified a signaling pathway regulated by LDLR expression: LDLR → phospholipase FAM83B → receptor tyrosine kinase FGFR family. Data from The Cancer Genome Atlas confirmed that this pathway is active in primary ovarian cancer tissue. Subsequent in vitro and in vivo chemo-sensitivity experiments revealed that this pathway contributes to resistance to platinum-based therapy.
LDLR → FAM83B → FGFR3 regulatory axis in cisplatin insensitivity:A Reduction of FAM83B mRNA and FGFR3 mRNA expression in endometrioid (MDAH-2774) and clear-cell (TOV-21G) ovarian cancer cell lines after LDLR-knockdown (shLDLR). B Tumor-suppressive effect of cisplatin (6 mg/kg/mice) in xenograft mouse models. Chang et al., ERC (2020), 10.1530/ERC-19-0095
Overall, this study revealed that overexpression of LDLR reduces sensitivity to platinum-based therapy in ovarian cancer cell lines and murine models. In the future, this finding may facilitate the development of therapies for ovarian cancer patients.
Lipotype Lipidomics technology can reveal molecular mechanisms involved in many biological processes, including various cancers, neurodegenerative diseases, metabolic diseases, and cardiovascular diseases. Future work may apply this strategy to examine other incompletely understood physiological and pathological phenomena.
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