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MALDI-MSI of lipids in a model of breast cancer brain metastasis provides a surrogate measure of ischemia/hypoxia

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Abstract

Breast cancer brain metastasis (BCBM) has an incidence of 10–30%. It is incurable and the biological mechanisms that promote its progression remain largely undefined. Consequently, to gain insights into BCBM processes, we have developed a spontaneous mouse model of BCBM and in this study found a 20% penetrance of macro-metastatic brain lesion formation. Considering that lipid metabolism is indispensable to metastatic progression, our goal was the mapping of lipid distributions throughout the metastatic regions of the brain. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) of lipids revealed that, relative to surrounding brain tissue, seven long-chain (13–21 carbons long) fatty acylcarnitines, as well as two phosphatidylcholines, two phosphatidylinositols two diacylglycerols, a long-chain phosphatidylethanolamine, and a long-chain sphingomyelin were highly concentrated in the metastatic brain lesion In broad terms, lipids known to be enriched in brain tissues, such as very long-chain (≥ 22 carbons in length) polyunsaturated fatty acid of phosphatidylcholines, phosphatidylethanolamine, sphingomyelins, sulfatides, phosphatidylinositol phosphates, and galactosylceramides, were not found or only found in trace amounts in the metastatic lesion and instead consistently detected in surrounding brain tissues. The data, from this mouse model, highlights an accumulation of fatty acylcarnitines as possible biological makers of a chaotic inefficient vasculature within the metastasis, resulting in relatively inadequate blood flow and disruption of fatty acid β-oxidation due to ischemia/hypoxia.

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Funding

This research was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, NIH. Venu Raman acknowledges support from Grant 1RO1CA207208.

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Author notes

  1. Aurelie Roux and Paul T. Winnard Jr have contributed equally to this study.

Authors and Affiliations

  1. Structural Biology Unit, Cellular Neurobiology Branch, Integrative Neuroscience NIDA-IRP, NIH, 333 Cassell Drive, Baltimore, MD, 21224, USA

    Aurelie Roux, Ludovic Muller, Shelley N. Jackson & Amina S. Woods

  2. Division of Cancer Imaging Research, Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Paul T. Winnard Jr, Marise Heerma Van Voss & Venu Raman

  3. Case Western Reserve University, Cleveland, OH, USA

    Barry Hoffer

  4. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Venu Raman

  5. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

    Venu Raman

  6. Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Amina S. Woods & Venu Raman

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  1. Aurelie Roux
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  2. Paul T. Winnard Jr
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Contributions

AR and MHVV designed and carried out the cell culture and animal experiments. PW generated the cell line, contributed to the writing and editing of main manuscript and contributed to the preparation of the figures. LM, SJ, BH, AR and AW designed and carried out the MALDI-MSI analysis. AR and AW contributed to the preparation of the figures and the writing and editing of the main manuscript. AW, VR designed the study and VR edited the manuscript.

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Correspondence to Amina S. Woods or Venu Raman.

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Roux, A., Winnard, P.T., Van Voss, M.H. et al. MALDI-MSI of lipids in a model of breast cancer brain metastasis provides a surrogate measure of ischemia/hypoxia. Mol Cell Biochem 478, 2567–2580 (2023). https://doi.org/10.1007/s11010-023-04685-4

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