Megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) promotes glioblastoma cell invasion in the brain microenvironment

Abstract

Glioblastoma (GBM), or grade IV astrocytoma, is a malignant brain cancer that contains subpopulations of proliferative and invasive cells that coordinately drive primary tumor growth, progression, and recurrence after therapy. Here, we have analyzed functions for megalencephalic leukoencephalopathy with subcortical cysts 1 (Mlc1), an eight-transmembrane protein normally expressed in perivascular brain astrocyte end feet that is essential for neurovascular development and physiology, in the pathogenesis of GBM. We show that Mlc1 is expressed in human stem-like GBM cells (GSCs) and is linked to the development of primary and recurrent GBM. Genetically inhibiting MLC1 in GSCs using RNAi-mediated gene silencing results in diminished growth and invasion in vitro as well as impaired tumor initiation and progression in vivo. Biochemical assays identify the receptor tyrosine kinase Axl and its intracellular signaling effectors as important for MLC1 control of GSC invasive growth. Collectively, these data reveal key functions for MLC1 in promoting GSC growth and invasion, and suggest that targeting the Mlc1 protein or its associated signaling effectors may be a useful therapy for blocking tumor progression in patients with primary or recurrent GBM.

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Fig. 1: MLC1 is expressed in primary human GSCs.
Fig. 2: MLC1 promotes GSC spheroid formation in vitro.
Fig. 3: MLC1 promotes GSC polarity and invasion in vitro.
Fig. 4: RPPA analysis of MLC1-regulated signaling pathways in GSCs.
Fig. 5: MLC1 promotes GSC invasive growth in the brain microenvironment.
Fig. 6: Analysis of Mlc1 protein expression in human GBM tissue samples.
Fig. 7: Analysis of Mlc1 protein expression in primary and recurrent human GBM samples.
Fig. 8: A model for Mlc1 control of GBM cell polarity and invasive growth in the brain microenvironment.

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Acknowledgements

We thank the various members of the McCarty laboratory for insightful comments on the paper. This work was supported, in part, by grants to JHM from the Cancer Prevention and Research Institute of Texas (RP180220), the National Institutes of Health (R01NS087635, R21NS103841, and P50CA127001), the Brockman Foundation, and the Terry L. Chandler Foundation. The following NCI-funded Cancer Center Support Grant (CCSG) Core Facilities were instrumental in data acquisition: the shRNA and ORFeome Core, the Research Histopathology Facility, the Flow Cytometry and Cellular Imaging Facility, and the Sequencing and Microarray Facility.

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Correspondence to Joseph H. McCarty.

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Lattier, J.M., De, A., Chen, Z. et al. Megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) promotes glioblastoma cell invasion in the brain microenvironment. Oncogene (2020). https://doi.org/10.1038/s41388-020-01503-9

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