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| Status |
Public on Sep 01, 2024 |
| Title |
Lipid saturation homeostasis presents a targetable vulnerability in MYC-amplified Group 3 medulloblastoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
300,000 SU_MB002 cells were treated with 4nM CAY10566 or DMSO for 72 hrs (two replicates each). Total RNA was isolated and then sequenced using Illumina NextSeq 2000.
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| Contributor(s) |
Custers S, Escudero L, Suk Y, McKenna D, Mobilio D, Bakhshinyan D, Apel E, Miletic P, Gwynne WD, Zhai K, Chafe SC, Brown K, Venugopal C, Moffat J, Singh SK |
| Citation missing |
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| Submission date |
Mar 14, 2024 |
| Last update date |
Sep 01, 2024 |
| Contact name |
Sheila Singh |
| E-mail(s) |
ssingh@mcmaster.ca
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| Organization name |
McMaster University
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| Department |
Biochemistry and Biomedical Sciences
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| Street address |
1280 Main Street West
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| City |
Hamilton |
| State/province |
ON |
| ZIP/Postal code |
L8S4K1 |
| Country |
Canada |
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| Platforms (1) |
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