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Lipid saturation homeostasis presents a targetable vulnerability in MYC-amplified Group 3 medulloblastoma

ABSTRACT: Medulloblastoma (MB) is the most common malignant pediatric brain cancer, originating from the cerebellum. Despite advancements in standard of care (SoC), MB remains fatal for 30% of patients. Tumor relapse, spinal metastasis and treatment resistance are the most prevalent in MYC-driven Group 3 MB (G3-MB). Patients surviving SoC are faced with life-long neurocognitive and neurodevelopmental deficits. These issues highlight the urgent need for improved treatment modalities. Reprogramming of cellular lipid metabolism is an emerging hallmark of cancer and may yield novel cancer-specific therapeutic options. Here we explore the lipidome of both G3-MB and its proposed cell of origin, human neural stem cells (hNSCs) by comparing untargeted lipidomics using Liquid-Chromatography-Mass Spectrometry (LC-MS). Comparative analyses revealed a differential abundance of distinct lipid species in G3-MB, with an overall reduced saturation level of fatty acids (FAs). These findings implicate the de novo lipid synthesis (DNL) pathway. We identified the enzymes involved in DNL to be essential for MB survival in our genome-wide CRISPR KO screen. Additionally, mRNA expression of the DNL enzymes increases at relapse in our SoC-adapted murine patient-derived xenograft (PDX) model. Pharmacological and genetic targeting of the DNL enzyme Stearoyl-CoA Desaturase 1 (SCD1) selectively targets G3-MB. Furthermore, small molecule treatment of SCD1 demonstrates efficacy against G3-MB PDX models in vivo. We identified SCD expression as a prognostic marker in Group 3 and 4 MB patients and identified possible pathways for MB treatment. Overall, these findings indicate that SCD1 is a potent target for the treatment of G3-MB.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261568 | GEO | 2024/09/01

REPOSITORIES: GEO

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Project description:Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with group 3 (G3) MB representing the most aggressive subgroup associated with a poor prognosis and a remarkable ability to resist upfront multimodal therapy. Despite a low mutational burden of disease and MYC amplification identified as a independent factor associated with poor survivorship, efforts to target the MYC has met with limited therapeutic success. Consequently alternative mediators associated with the aggressive phenotype of G3 MB continues as a common goal within the MB community. Here we show how the neural stem cell determinant Musashi 1 (MSI1) is a central and vital moderator of G3 MB in both a MYC amplified mouse model of G3 MB and patient derived xenografts (PDX). Specifically, we modified the MYC amplified and p53 mutated (MP) mouse model of G3 MB to generate Msi1 conditional knockout mice (Msi1flox/flox), which led to the observation that MSI1 is required for tumor initiation of MP tumors. To identify the translational potential of these findings, we employed shRNA against Msi1 in multiple PDX lines, observing a striking deficit in multiple key stem cell features including self-renewal, proliferation, and failure to progress through the cell cycle. Notably, Msi1 inhibition resulted in a failure of tumor initiation, translating to a significantly prolonged survival, reaffirming the essential role for MSI1 in G3 MB. To determine how MSI1 symphonizes the anarchic post-transcriptional landscape of G3MB, we differentially analyzed the MSI1 binding sites in normal neural stem cells and G3 MB and subsequently compared the MSI1-binding transcriptome, and proteome following Msi1 inhibition. Comparative analysis suggested an integral role for post-transcriptional regulators, such as MSI1 and its binding prey mRNA, as a therapeutic target. Here we propose the neural RNA binding protein MSI1, as a master regulator, hijacked from its normal neural developmental function, orchestrating the aberrant translational landscape of G3 MB.

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Lipid saturation homeostasis presents a targetable vulnerability in MYC-amplified Group 3 medulloblastoma

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