NOTCH3 Drives Fatty Acid Oxidation and Ferroptosis Resistance in Aggressive Meningiomas Article Swipe
Nishanth S. Sadagopan
,
Mateo Gomez
,
Ian Olson
,
Leah K. Billingham
,
Shashwat Tripathi
,
Martha A. Cady
,
Harrshavasan Congivaram
,
Tzu-Yi Chia
,
Hanxiao Wan
,
Si Wang
,
David R. Raleigh
,
Faith C. Kaluba
,
Evan C. Lien
,
Amy B. Heimberger
,
Catalina Lee-Chang
,
Mark W. Youngblood
,
Stephen T. Magill
,
Jason Miska
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-6779386/v1
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-6779386/v1
PURPOSE NOTCH3 is increasingly implicated for its oncogenic role in many malignancies, including meningiomas. While prior work has linked NOTCH3 expression to higher-grade meningiomas and treatment resistance, the metabolic phenotype of NOTCH3 activation remains unexplored in meningioma. METHODS We performed single-cell RNA sequencing on NOTCH3 + human meningioma cell lines. Using the CH157-MN meningioma cell model, we overexpressed NOTCH3 intracellular domain (ICD) and performed untargeted metabolomic, lipidomic, and bulk RNA sequencing analyses as well as functional metabolic assays. RESULTS We show that NOTCH3 mediates a metabolic shift towards fatty acid oxidation (FAO), depleting lipid availability and conferring resistance to ferroptosis. Single-cell RNA sequencing revealed a correlation with CD36, a key fatty acid transporter. Furthermore, patient-derived primary meningioma lines stratified by NOTCH3 expression confirmed higher CD36 expression and increased maximal mitochondrial respiration in NOTCH3-high cells in the presence of palmitate, supporting enhanced FAO. NOTCH3 ICD overexpression (OE) exhibited depletion of fatty acid pools, alongside transcriptional upregulation of canonical FAO genes. Functional mitochondrial assays confirmed elevated oxidative respiration in the presence of palmitate compared with controls. Additionally, NOTCH3 OE cells exhibit increased resistance to RSL3-induced ferroptosis, a phenotype that was reversed with CPT1. CONCLUSION These data establish a link between NOTCH3 signaling, lipid metabolic reprogramming, and ferroptosis evasion in aggressive meningioma cells. This metabolic shift may contribute to the malignant behavior observed in NOTCH3 + meningiomas, offering new insight into the biochemical vulnerabilities of these tumors.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.21203/rs.3.rs-6779386/v1
- https://www.researchsquare.com/article/rs-6779386/latest.pdf
- OA Status
- gold
- References
- 44
- Related Works
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- OpenAlex ID
- https://openalex.org/W4411036897
All OpenAlex metadata
Raw OpenAlex JSON
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https://openalex.org/W4411036897Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.21203/rs.3.rs-6779386/v1Digital Object Identifier
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NOTCH3 Drives Fatty Acid Oxidation and Ferroptosis Resistance in Aggressive MeningiomasWork title
- Type
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preprintOpenAlex work type
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-06-04Full publication date if available
- Authors
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Nishanth S. Sadagopan, Mateo Gomez, Ian Olson, Leah K. Billingham, Shashwat Tripathi, Martha A. Cady, Harrshavasan Congivaram, Tzu-Yi Chia, Hanxiao Wan, Si Wang, David R. Raleigh, Faith C. Kaluba, Evan C. Lien, Amy B. Heimberger, Catalina Lee-Chang, Mark W. Youngblood, Stephen T. Magill, Jason MiskaList of authors in order
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https://doi.org/10.21203/rs.3.rs-6779386/v1Publisher landing page
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https://www.researchsquare.com/article/rs-6779386/latest.pdfDirect link to full text PDF
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://www.researchsquare.com/article/rs-6779386/latest.pdfDirect OA link when available
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Biology, CD36, Genetics, GeneTop concepts (fields/topics) attached by OpenAlex
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10Other works algorithmically related by OpenAlex
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| primary_location.id | doi:10.21203/rs.3.rs-6779386/v1 |
| primary_location.is_oa | True |
| primary_location.source | |
| primary_location.license | cc-by |
| primary_location.pdf_url | https://www.researchsquare.com/article/rs-6779386/latest.pdf |
| primary_location.version | acceptedVersion |
| primary_location.raw_type | posted-content |
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| primary_location.landing_page_url | https://doi.org/10.21203/rs.3.rs-6779386/v1 |
| publication_date | 2025-06-04 |
| publication_year | 2025 |
| referenced_works | https://openalex.org/W1484840368, https://openalex.org/W2067250364, https://openalex.org/W2078767245, https://openalex.org/W2171623512, https://openalex.org/W2026827095, https://openalex.org/W1963808889, https://openalex.org/W2893020530, https://openalex.org/W2021556801, https://openalex.org/W2170400030, https://openalex.org/W1584770604, https://openalex.org/W2518288696, https://openalex.org/W2049449372, https://openalex.org/W4309246250, https://openalex.org/W4396893469, https://openalex.org/W2341031032, https://openalex.org/W4229451105, https://openalex.org/W4229449309, https://openalex.org/W2794480084, https://openalex.org/W2984472267, https://openalex.org/W2802963454, https://openalex.org/W4403638517, https://openalex.org/W3003572520, https://openalex.org/W1974356017, https://openalex.org/W2119375033, https://openalex.org/W2810583651, https://openalex.org/W2801288105, https://openalex.org/W4291903976, https://openalex.org/W4306746303, https://openalex.org/W4377565462, https://openalex.org/W4392468516, https://openalex.org/W2107542389, https://openalex.org/W4224226256, https://openalex.org/W2772250549, https://openalex.org/W2885029979, https://openalex.org/W3028827854, https://openalex.org/W2995654976, https://openalex.org/W4389993180, https://openalex.org/W4391222250, https://openalex.org/W4404011373, https://openalex.org/W1997183854, https://openalex.org/W4226367800, https://openalex.org/W4391878282, https://openalex.org/W4392757206, https://openalex.org/W4221073061 |
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| abstract_inverted_index.by | 120 |
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| abstract_inverted_index.and | 25, 63, 68, 96, 127, 204 |
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| abstract_inverted_index.its | 7 |
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| abstract_inverted_index.FAO. | 142 |
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| abstract_inverted_index.fatty | 89, 111, 150 |
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| abstract_inverted_index.lipid | 94, 201 |
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| abstract_inverted_index.lines. | 50 |
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| abstract_inverted_index.palmitate, | 139 |
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| abstract_inverted_index.sequencing | 43, 71, 103 |
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