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IgG based immunome analyses of breast cancer patients reveal underlying signaling pathways.

ABSTRACT: Background: Breast cancer is the most frequent and one of the most fatal malignancies among women. Within the concept of personalized medicine, molecular characterization of tumors is usually performed by analyzing somatic mutations, RNA gene expression signatures or the proteome by mass-spectrometry. Alternatively, the immunological fingerprint of the patients can be analyzed by protein microarrays, which is able to provide another layer of molecular pathological information without invasive intervention. Results: We have investigated the immune signature of breast cancer patients and compared them with healthy controls, using protein microarray-based IgG profiling. The identified differentially reactive antigens (n=517) were further evaluated by means of various pathway analysis tools. Our results indicate that the immune signature of breast cancer patients shows a clear distinction from healthy individuals characterized by differentially reactive antigens involved in known disease relevant signaling pathways, such as VEGF, AKT/PI3K/mTOR or c-KIT, which is in close agreement with the findings from RNA-based expression profiles. Conclusion: Differential antigenic properties between breast cancer patients and healthy individual classes can be defined by serum-IgG profiling on protein microarrays. These immunome profiles provide an additional layer of molecular pathological information, which has the potential to refine and complete the systems biological map of neoplastic disease.

SUBMITTER: Gyurjan I

PROVIDER: S-EPMC6544406 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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IgG based immunome analyses of breast cancer patients reveal underlying signaling pathways.

Gyurján István I Rosskopf Sandra S Coronell Johana A Luna JAL Muhr Daniela D Singer Christian C Weinhäusel Andreas A

Oncotarget 20190528 37

<b>Background:</b> Breast cancer is the most frequent and one of the most fatal malignancies among women. Within the concept of personalized medicine, molecular characterization of tumors is usually performed by analyzing somatic mutations, RNA gene expression signatures or the proteome by mass-spectrometry. Alternatively, the immunological fingerprint of the patients can be analyzed by protein microarrays, which is able to provide another layer of molecular pathological information without inva ...[more]

PMID: 31191821

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Project description:ClpP activators ONC201 and related small molecules (TR compounds, Madera Therapeutics), have demonstrated significant anti-cancer potential in vitro and in vivo studies, including clinical trials for refractory solid tumors. Though progress has been made in identifying specific phenotypic outcomes following ClpP activation, the exact mechanism by which ClpP activation leads to broad anti-cancer activity has yet to be fully elucidated. In this study, we utilized a multi-omics approach to identify the ClpP-dependent proteomic, transcriptomic, and metabolomic changes resulting from ONC201 or the TR compound TR-57 in triple-negative breast cancer cells. Applying mass spectrometry-based methods of proteomics and metabolomics, we identified ∼8,000 proteins and 588 metabolites, respectively. From proteomics data, 113 (ONC201) and 191 (TR-57) proteins significantly increased and 572 (ONC201) and 686 (TR-57) proteins significantly decreased in this study. Gene ontological (GO) analysis revealed strong similarities between proteins up- or downregulated by ONC201 or TR-57 treatment. Notably, this included the downregulation of many mitochondrial processes and proteins, including mitochondrial translation and mitochondrial matrix proteins. We performed a large-scale transcriptomic analysis of WT SUM159 cells, identifying ∼7,700 transcripts (746 and 1,100 significantly increasing, 795 and 1,013 significantly decreasing in ONC201 and TR-57 treated cells, respectively). Less than 21% of these genes were affected by these compounds in ClpP null cells. GO analysis of these data demonstrated additional similarity of response to ONC201 and TR-57, including a decrease in transcripts related to the mitochondrial inner membrane and matrix, cell cycle, and nucleus, and increases in other nuclear transcripts and transcripts related to metal-ion binding. Comparison of response between both compounds demonstrated a highly similar response in all -omics datasets. Analysis of metabolites also revealed significant similarities between ONC201 and TR-57 with increases in α-ketoglutarate and 2-hydroxyglutaric acid and decreased ureidosuccinic acid, L-ascorbic acid, L-serine, and cytidine observed following ClpP activation in TNBC cells. Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation.

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IgG based immunome analyses of breast cancer patients reveal underlying signaling pathways.

Publications

IgG based immunome analyses of breast cancer patients reveal underlying signaling pathways.

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