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Multiomics Analysis of Cancer Chemotherapy Sensitivity

Research Article LDLR expression influences ovarian cancer cells’ sensitivity to platinum-based chemotherapy.

About the authors


Henri Deda and
Nuala Del Piccolo
Henri Deda
Communications Officer

Henri Deda holds a degree in Molecular Bioengineering. He is spirited to discover what scientists are interested in and to provide concise answers.


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.

Resources


LDLR-mediated lipidome–transcriptome…

Chang et al. | ERC (2020)


Mouse lipidomics reveals inherent flexibility…

Surma et al. | SciRep (2021)


Systematic screening for novel lipids by…

Papan et al. | Anal. Chem. (2014)


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A medical model of the female reproductive organ system.

Summary

• 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

Authors
Henri Deda and
Nuala Del Piccolo

OVARIAN cancer, found in the female gland that produces eggs, is among the most common cancers worldwide. The disease can display characteristic features of cancer, such as genetic mutations, hypoxia, and angiogenesis. Like other solid tumors, ovarian cancer is frequently treated with platinum-based chemotherapies such as cisplatin. However, the response to this therapy is variable and new therapies and/or treatment courses are researched.

An infographic showing the cellular origins of serous ovarian cancer, mucinous ovarian cancer, endometrioid ovarian cancer, and clear cell ovarian cancer.

Ovarian cancers can be classified into four subtypes – serous, mucinous, endometrioid, and clear-cell – based on their histology. These 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, and sensitivity to platinum-based chemotherapy. The study’s results indicate that LDLR expression influences chemo-sensitivity.

An infographic depicting LDLR-mediated endocytosis. LDL particles containing cholesterol are binding to LDL receptors of the cell membrane. A clathrin-coated pit is formed and engulfs the LDL particle to create an endosome. The endosome fuses with a lysosome and the degradation of the LDL particle into amino acids, fatty acids, and cholesterol begins.

The four ovarian cancer subtypes – serous, mucinous, endometrioid, and clear-cell – were modeled using cell lines, murine models, fixed patient tissue samples, and data from The Cancer Genome Atlas. These models were characterized via viability, chemosensitivity, lipidomic, and transcriptomic assays.

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.

(A) Immunohistochemistry staining of LDLR. (B) Quantitation of Immunohistochemistry scores (IHC scores) of LDLR. The patient numbers are serous (S, n = 16), mucinous (M, n = 29), endometrioid (E, n = 50), and clear-cell (C, n = 20). ‘Strong’ indicates an IHC score of 3 or above; ‘weak’ indicates an IHC score lower than 3.

LDLR expression in ovarian cancer subtypes: A Immunohistochemistry staining of LDLR. B Quantitation of Immunohistochemistry scores (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), doi: 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.

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.

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), doi: 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 upregulated expression of lyso-phosphatidylcholine, downregulated expression of ether-linked phosphatidylethanolamine, and altered the expression of 1404 genes.

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.

(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.

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), doi: 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 inform the development of therapies and/or treatment courses for ovarian cancer patients.

Multiomics analyses of gene, lipid, phenotype, and other biological data can reveal molecular mechanisms involved in many biological processes, including ovarian cancer chemo-sensitivity, Alzheimer’s disease, type I diabetes, and cardiovascular disease. Future work may apply this strategy to examine other incompletely understood physiological and pathological phenomena.

Lipotype Lipidomics technology can characterize the lipid profile of in vitro cell culture samples. This approach has provided new insight on diseases like ovarian cancer; biological processes like the mitochondrial unfolded protein response; and biophysical properties like membrane fluidity.

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China Medical University Hospital


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China Medical University Hospital aims to speed up integration of interdisciplinary medical research results into clinical healthcare. Key scientific fields include research in the areas of cancer, genetics and gene therapy, proteome, molecular medicine, Chinese Materia Medica, and stem cells.


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