Lipidome signatures of metastasis in a transgenic mouse model of sonic hedgehog medulloblastoma
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RESEARCH PAPER
Lipidome signatures of metastasis in a transgenic mouse model of sonic hedgehog medulloblastoma Danning Huang 1 & Jingbo Liu 2 & Ronald C. Eldridge 3 & David A. Gaul 1 & Martin R. L. Paine 4 & Karan Uppal 5 & Tobey J. MacDonald 2 & Facundo M. Fernández 1 Received: 5 June 2020 / Revised: 17 July 2020 / Accepted: 21 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, has high propensity to metastasize. Currently, the standard treatment for MB patients includes radiation therapy administered to the entire brain and spine for the purpose of treating or preventing against metastasis. Due to this aggressive treatment, the majority of long-term survivors will be left with permanent and debilitating neurocognitive impairment, for the 30–40% patients that fail to respond to treatment, all will relapse with terminal metastatic disease. An understanding of the underlying biology that drives MB metastasis is lacking, and is critically needed in order to develop targeted therapeutics for its prevention. To examine the metastatic biology of sonic hedgehog (SHH) MB, the human MB subgroup with the worst clinical outcome in children, we first generated a robust SmoA1-Math-GFP mouse model that reliably reproduces human SHH MB whereby metastases can be visualized under fluorescence microscopy. Lipidome alterations associated with metastasis were then investigated by applying ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) under positive ionization mode to primary tumor samples collected from mice without (n = 18) and with (n = 7) metastasis. Thirty-four discriminant lipids associated with SHH MB metastasis were successfully annotated, including ceramides (Cers), sphingomyelins (SMs), triacylglycerols (TGs), diacylglycerols (DGs), phosphatidylcholines (PCs), and phosphatidic acids (PAs). This study provides deeper insights into dysregulations of lipid metabolism associated with SHH MB metastatic progression, and thus serves as a guide toward novel targeted therapies. Keywords Medulloblastoma . Metastasis . Non-targeted metabolomics . Ultra-performance liquid chromatography-mass spectrometry . Lipids
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00216-020-02837-9) contains supplementary material, which is available to authorized users. * Tobey J. MacDonald [email protected] * Facundo M. Fernández [email protected] 1
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA
2
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
3
Emory University School of Nursing, Atlanta, GA 30322, USA
4
ImaBiotech, 59120 Loos, France
5
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Medulloblastoma (MB) is an aggressive embryonal tumor that originates in the posterior fossa
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