Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination

Martirosian, Vahan; Deshpande, Krutika; Zhou, Hao; Shen, K. Robert; Smith, Kyle; Northcott, Paul A.; Lin, Michelle; Stepanosyan, Vazgen; Das, Diganta; Remšík, Ján; Isakov, Danielle; Boire, Adrienne; Feyter, Henk De; Hurth, Kyle; Li, Shaobo; Wiemels, Joseph L.; Nakamura, Brooke N.; Shao, Liang; Danilov, Camelia A.; Chen, Thomas; Neman, Josh

doi:10.1016/j.celrep.2021.109302

Cited by 24 publications

(13 citation statements)

References 96 publications

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“…Of interest, while differentiated neurons show both high OXPHOS rate and ABAT expression, neural stem cells and MB tumors exhibit low ABAT levels; notably, ABAT levels are lower in the metastatic G3/G4 subgroups compared to the less aggressive WNT/SHH subtypes. Intriguingly, during dissemination, MB cells exploit GABA metabolism to survive in the nutrient-poor environment of CSF, facilitating metastasis formation; this suggests a crucial role for ABAT expression fluctuation to promote leptomeningeal dissemination ( Martirosian et al, 2021 ).…”

Section: Metabolic Reprogramming In Medulloblastomamentioning

confidence: 99%

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Marabitti

Giansanti²,

Mitri³

et al. 2022

Front. Cell Dev. Biol.

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Tumor-specific alterations in metabolism have been recognized to sustain the production of ATP and macromolecules needed for cell growth, division and survival in many cancer types. However, metabolic heterogeneity poses a challenge for the establishment of effective anticancer therapies that exploit metabolic vulnerabilities. Medulloblastoma (MB) is one of the most heterogeneous malignant pediatric brain tumors, divided into four molecular subgroups (Wingless, Sonic Hedgehog, Group 3 and Group 4). Recent progresses in genomics, single-cell sequencing, and novel tumor models have updated the classification and stratification of MB, highlighting the complex intratumoral cellular diversity of this cancer. In this review, we emphasize the mechanisms through which MB cells rewire their metabolism and energy production networks to support and empower rapid growth, survival under stressful conditions, invasion, metastasis, and resistance to therapy. Additionally, we discuss the potential clinical benefits of currently available drugs that could target energy metabolism to suppress MB progression and increase the efficacy of the current MB therapies.

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Section: Metabolic Reprogramming In Medulloblastomamentioning

confidence: 99%

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Marabitti

Giansanti²,

Mitri³

et al. 2022

Front. Cell Dev. Biol.

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“…Consequently, metastatic tumors arising through this process contain a strong dependency on the SHH signaling pathway [ 150 ]. Furthermore, Martirosian and colleagues explained that metastatic MB cells use the enzyme GABA transaminase (ABAT) to survive in the nutrient-deficient CSF microenvironment by metabolizing GABA, an inhibitory neurotransmitter, as an energy source ( Figure 3 B) [ 154 ]. Through this mechanism, metastatic MB cells exploit differentiated GABAergic neuronal characteristics such as GABA metabolism, histone deacetylation, and decreased tumor cell proliferation, thereby promoting LMD.…”

Section: Targeting the Brain Tumor Vasculature In Medulloblastomamentioning

confidence: 99%

The Tumor Microenvironment of Medulloblastoma: An Intricate Multicellular Network with Therapeutic Potential

Bree

Wilhelm

2022

Cancers

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Medulloblastoma (MB) is a heterogeneous disease in which survival is highly affected by the underlying subgroup-specific characteristics. Although the current treatment modalities have increased the overall survival rates of MB up to 70–80%, MB remains a major cause of cancer-related mortality among children. This indicates that novel therapeutic approaches against MB are needed. New promising treatment options comprise the targeting of cells and components of the tumor microenvironment (TME). The TME of MB consists of an intricate multicellular network of tumor cells, progenitor cells, astrocytes, neurons, supporting stromal cells, microglia, immune cells, extracellular matrix components, and vasculature systems. In this review, we will discuss all the different components of the MB TME and their role in MB initiation, progression, metastasis, and relapse. Additionally, we briefly introduce the effect that age plays on the TME of brain malignancies and discuss the MB subgroup-specific differences in TME components and how all of these variations could affect the progression of MB. Finally, we highlight the TME-directed treatments, in which we will focus on therapies that are being evaluated in clinical trials.

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“…Relapses occur in 30% MB patients after surgery, and the metastasis rate and the 3 years survival rate of relapsed patients are 86% and 18% [ 6 ]. Metastatic cells detach from primary tumors and disseminate to the leptomeninges by passive spread through the cerebrospinal fluid or to the brain or other organs through a hematogenous route [ 7 , 8 ]. Although the molecular mechanisms of MB primary tumors are well elucidated, the molecular defects underlying metastasis are still unclear.…”

Section: Introductionmentioning

confidence: 99%

AMPK attenuates SHH subgroup medulloblastoma growth and metastasis by inhibiting NF-κB activation

Cai

Wang

et al. 2023

Cell Biosci

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Background Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Metastasis and relapse are the leading causes of death in MB patients. The initiation of the SHH subgroup of MB (SHH-MB) is due to the aberrant activation of Sonic Hedgehog (Shh) signaling. However, the mechanisms for its metastasis are still unknown. Results AMP-dependent protein kinase (AMPK) restrains the activation of Shh signaling pathway, thereby impeding the proliferation of SHH-MB cells. More importantly, AMPK also hinders the growth and metastasis of SHH-MB cells by regulating NF-κB signaling pathway. Furthermore, Vismodegib and TPCA-1, which block the Shh and NF-κB pathways, respectively, synergistically restrained the growth, migration, and invasion of SHH-MB cells. Conclusions This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-κB. AMPK-NF-κB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-κB and Shh pathways confers synergy for SHH-MB therapy.

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Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination

Cited by 24 publications

References 96 publications

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

The Tumor Microenvironment of Medulloblastoma: An Intricate Multicellular Network with Therapeutic Potential

AMPK attenuates SHH subgroup medulloblastoma growth and metastasis by inhibiting NF-κB activation

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