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Open AccessArticle

Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid

1
Institute of Analytical Chemistry, Johannes Kepler University, Altenberger Strasse 69, 4040 Linz, Austria
2
Department of Analytical Chemistry, University of Vienna, Waehringer Straße 38, 1090 Vienna, Austria
3
Joint Metabolome Facility, Faculty of Chemistry, University of Vienna, Waehringer Straße 38, 1090 Vienna, Austria
4
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(6), 1350; https://doi.org/10.3390/cancers12061350
Received: 6 April 2020 / Revised: 7 May 2020 / Accepted: 22 May 2020 / Published: 26 May 2020
(This article belongs to the Section Tumor Microenvironment)
Molecular classification of medulloblastoma (MB) is well-established and reflects the cell origin and biological properties of tumor cells. However, limited data is available regarding the MB tumor microenvironment. Here, we present a mass spectrometry-based multi-omics pilot study of cerebrospinal fluid (CSF) from recurrent MB patients. A group of age-matched patients without a neoplastic disease was used as control cohort. Proteome profiling identified characteristic tumor markers, including FSTL5, ART3, and FMOD, and revealed a strong prevalence of anti-inflammatory and tumor-promoting proteins characteristic for alternatively polarized myeloid cells in MB samples. The up-regulation of ADAMTS1, GAP43 and GPR37 indicated hypoxic conditions in the CSF of MB patients. This notion was independently supported by metabolomics, demonstrating the up-regulation of tryptophan, methionine, serine and lysine, which have all been described to be induced upon hypoxia in CSF. While cyclooxygenase products were hardly detectable, the epoxygenase product and beta-oxidation promoting lipid hormone 12,13-DiHOME was found to be strongly up-regulated. Taken together, the data suggest a vicious cycle driven by autophagy, the formation of 12,13-DiHOME and increased beta-oxidation, thus promoting a metabolic shift supporting the formation of drug resistance and stem cell properties of MB cells. In conclusion, the different omics-techniques clearly synergized and mutually supported a novel model for a specific pathomechanism. View Full-Text
Keywords: cerebrospinal fluid; oxylipins; hypoxia; lipidomics; mass spectrometry; medulloblastoma; metabolomics; multi-omics; polarized macrophages; proteomics cerebrospinal fluid; oxylipins; hypoxia; lipidomics; mass spectrometry; medulloblastoma; metabolomics; multi-omics; polarized macrophages; proteomics
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MDPI and ACS Style

Reichl, B.; Niederstaetter, L.; Boegl, T.; Neuditschko, B.; Bileck, A.; Gojo, J.; Buchberger, W.; Peyrl, A.; Gerner, C. Determination of a Tumor-Promoting Microenvironment in Recurrent Medulloblastoma: A Multi-Omics Study of Cerebrospinal Fluid. Cancers 2020, 12, 1350.

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