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

Lattier, John; De, Arpan; Chen, Zhihua; Morales, John E.; Lang, Frederick F.; Huse, Jason T.; McCarty, Joseph H.

doi:10.1038/s41388-020-01503-9

Cited by 13 publications

(14 citation statements)

References 48 publications

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“…GBM is the most aggressive and lethal brain tumor and has a worse outcome in humans. The major obstacle for GBM treatment is diffuse tumor cell invasion and ensuing metastasis, which cause glioma cells migrate away from the tumor core area and escape the complete surgical resection, and partially avoid chemo- and radiotherapy, and to further cause tumor recurrence [ 31 , 36 , 37 ]. Therefore, new targets that regulate the invasion process are urgently needed and are actively being pursued [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

TMEM158 promotes the proliferation and migration of glioma cells via STAT3 signaling in glioblastomas

Wang

Chen

et al. 2022

Cancer Gene Ther

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Glioblastoma is the most common primary intracranial malignant tumor in adults and has high morbidity and high mortality. TMEM158 has been reported to promote the progression of solid tumors. However, its potential role in glioma is still unclear. Here, we found that TMEM158 expression in human glioma cells in the tumor core was significantly higher than that in noncancerous cells at the tumor edge using bioinformatics analysis. Cancer cells in patients with primary GBMs harbored significantly higher expression of TMEM158 than those in patients with WHO grade II or III gliomas. Interestingly, regardless of tumor grading, human glioma samples that were IDH1-wild-type (IDH1-WT) exhibited higher expression of TMEM158 than those with IDH1-mutant (IDH1-Mut). We also illustrated that TMEM158 mRNA expression was correlated with poor overall survival in glioma patients. Furthermore, we demonstrated that silencing TMEM158 inhibited the proliferation of glioma cells and that TMEM158 overexpression promoted the migration and invasion of glioma cells by stimulating the EMT process. We found that the underlying mechanism involves STAT3 activation mediating TMEM158-driven glioma progression. In vivo results further confirmed the inhibitory effect of the TMEM158 downregulation on glioma growth. Collectively, these findings further our understanding of the oncogenic function of TMEM158 in gliomas, which represents a potential therapeutic target, especially for GBMs.

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Section: Discussionmentioning

confidence: 99%

TMEM158 promotes the proliferation and migration of glioma cells via STAT3 signaling in glioblastomas

Wang

Chen

et al. 2022

Cancer Gene Ther

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“…MLC1 is the regulatory constituent of the PM macromolecular signaling cluster, which is pertinent for astrocytes homeostasis, motility/morphology [29][30][31], inflammatory responses [32], signaling and regulation of the brain extracellular space ion homeostasis [33][34][35]. The integral membrane protein constituents of the cluster are; Na + /K + -ATPase, TRPV4 cation and ClC-2 chloride channels, EGF receptor and the GlialCAM adhesion molecules [36][37][38][39].…”

Section: Introductionmentioning

confidence: 99%

Ubr1-induced selective endophagy/autophagy protects against the endosomal and Ca2+-induced proteostasis disease stress

Wang

Isenmann

et al. 2022

Cell. Mol. Life Sci.

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The cellular defense mechanisms against cumulative endo-lysosomal stress remain incompletely understood. Here, we identify Ubr1 as a protein quality control (QC) E3 ubiquitin-ligase that counteracts proteostasis stresses by facilitating endosomal cargo-selective autophagy for lysosomal degradation. Astrocyte regulatory cluster membrane protein MLC1 mutations cause endosomal compartment stress by fusion and enlargement. Partial lysosomal clearance of mutant endosomal MLC1 is accomplished by the endosomal QC ubiquitin ligases, CHIP and Ubr1 via ESCRT-dependent route. As a consequence of the endosomal stress, a supportive QC mechanism, dependent on both Ubr1 and SQSTM1/p62 activities, targets ubiquitinated and arginylated MLC1 mutants for selective endosomal autophagy (endophagy). This QC pathway is also activated for arginylated Ubr1-SQSTM1/p62 autophagy cargoes during cytosolic Ca2+-assault. Conversely, the loss of Ubr1 and/or arginylation elicited endosomal compartment stress. These findings underscore the critical housekeeping role of Ubr1 and arginylation-dependent endophagy/autophagy during endo-lysosomal proteostasis perturbations and suggest a link of Ubr1 to Ca2+ homeostasis and proteins implicated in various diseases including cancers and brain disorders.

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“…MLC1 has also been linked to EGFR signaling in low-grade human gliomas harboring R132H mutations in the IDH1 gene Hence, it is enticing to speculate the loss of HEPACAM in GBM cells causes an imbalance in RTK expression and/or signaling via Mlc1. However, the RPPA analyses identify connections between hepaCAM, integrins, and focal adhesion components, which do not overlap with RPPA pathways regulated by Mlc1 in GSCs (10), suggesting that hepaCAM functions at least partially independently of Mlc1 in GSCs.…”

Section: Discussionmentioning

confidence: 99%

HepaCAM Suppresses Glioblastoma Stem Cell Invasion in the Brain

Lattier

Morales

et al. 2022

Preprint

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Glioblastoma (GBM) is a malignant brain cancer that contains sub-populations of highly invasive tumor cells that drive progression and recurrence after surgery and radiochemotherapy. The exact mechanisms that enable GBM cells to disperse from the main tumor mass and navigate throughout the brain microenvironment remain largely unknown. As a result, there is a lack of effective strategies to block cancer cell invasive growth in primary and recurrent GBM. Here we report that hepatocyte cell adhesion molecule (hepaCAM), which is normally expressed in perivascular astrocytes, plays central roles in controlling the invasive growth features of GBM cells. Genetically targeting HEPACAM induces a transition from GBM cell proliferation/self-renewal to invasion. Increased invasion is due, in part, to an activation of focal adhesion signaling pathways and enhanced GBM cell adhesion to the extracellular matrix (ECM) in the brain microenvironment. Transcriptional profiling of GBM cells reveals various HEPACAM-regulated genes with links to polarity and invasion. Collectively, these data show that hepaCAM balances ECM adhesion and signaling pathways to control cancer cell proliferation versus invasion in the brain parenchyma. Targeting select components of the hepaCAM pathway may be an effective way to block tumor progression and recurrence in patients with GBM.

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

Cited by 13 publications

References 48 publications

TMEM158 promotes the proliferation and migration of glioma cells via STAT3 signaling in glioblastomas

TMEM158 promotes the proliferation and migration of glioma cells via STAT3 signaling in glioblastomas

Ubr1-induced selective endophagy/autophagy protects against the endosomal and Ca2+-induced proteostasis disease stress

HepaCAM Suppresses Glioblastoma Stem Cell Invasion in the Brain

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