Low carbohydrate high fat diet curbs glioblastoma by shifting lipids and limiting cancer stem cell metabolic flexibility | Communications Biology

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Low carbohydrate high fat diet curbs glioblastoma by shifting lipids and limiting cancer stem cell metabolic flexibility

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Abstract<br>Metabolic rewiring fuels tumorigenicity of cancer stem cells contributing to universal glioblastoma (GBM) recurrence. Invasive glioblastoma stem cells (GSCs), already unresectable, acquire tumorigenic properties that confer therapy resistance. Using samples from both recurrent and newly diagnosed GBM patients, we identified fatty acid oxidation (FAO) as a key pathway supporting GSC tumorigenicity. Transcriptomic profiling, compared against non-malignant human astrocytes from epilepsy patients, highlighted an FAO-enriched signature in GSCs. In vivo studies showed that tumor formation by these GSCs could be modulated by altering the availability of metabolizable lipids in the brain, with beneficial effects observed under a low carbohydrate high fat diet (LCHFD). The lipid metabolism contributing to GSC mediated tumor formation was confirmed using metabolomic and lipidomic analyses. Gut microbiome analyses revealed that LCHFD shapes the microbiome and modulates the circadian network. By targeting FAO in the postoperative period before chemoradiation, LCHFD offers a non-pharmacologic strategy to delay GBM recurrence. This study suggests a mechanistic framework for dietary modulation as a therapeutic approach to improve GBM outcomes.

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CNS cancer

Acknowledgements<br>We thank Dr. Akil Kalathil for technical help during one of our in vivo studies and Dr. Eva M. Medina-Rodriguez for one of our neurobehavior analyses studies.

Funding<br>S.D. discloses support for the research of this work from Florida Department of Health Casey DeSantis Florida Cancer Innovation Fund (25C44), and bridge funding from Sylvester Comprehensive Cancer Center. We also thank Sylvester Comprehensive Cancer Center, the NCI funded Sylvester Comprehensive Cancer Center support grant 1P30CA240139. We thank the Cancer Modeling Shared Resource (CMSR RRID: SCR022891), and NIH grant 1S10OD023579-01 for the VS120 Slide Scanner.

Author information<br>Author notesThese authors contributed equally: Shrita Sarkar, Akash Ashokan, Bapurao Surnar.

Authors and Affiliations<br>Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA<br>Shrita Sarkar, Akash Ashokan, Bapurao Surnar, Bhabatosh Banik, Daniel C. Bilbao, Eléonore Beurel & Shanta Dhar

Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA<br>Akash Ashokan, Stefano Lepore, Ricardo J. Komotar, Daniel C. Bilbao, Michael E. Ivan & Shanta Dhar

Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA<br>Daniel G. Eichberg, Tatiana I. Slepak, Ricardo J. Komotar & Michael E. Ivan

Department of Biochemistry and Molecular Pharmacology, NYU Langone Medical Center, New York, NY, USA<br>Lia Ficaro & Drew R. Jones

Department of Pathology and Laboratory Medicine, University of Miami School of Medicine, Miami, FL, USA<br>Daniel C. Bilbao

Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA<br>Eléonore Beurel

AuthorsShrita SarkarView author publications<br>Search author on:PubMed Google Scholar

Akash AshokanView author publications<br>Search author on:PubMed Google Scholar

Bapurao SurnarView author publications<br>Search author on:PubMed Google Scholar

Bhabatosh BanikView author publications<br>Search author on:PubMed Google Scholar

Daniel G. EichbergView author publications<br>Search author on:PubMed Google Scholar

Stefano LeporeView author publications<br>Search author on:PubMed Google Scholar

Lia FicaroView author publications<br>Search author on:PubMed Google Scholar

Tatiana I. SlepakView author publications<br>Search author on:PubMed Google Scholar

Ricardo J. KomotarView author publications<br>Search author on:PubMed Google Scholar

Drew R. JonesView author publications<br>Search author on:PubMed Google Scholar

Daniel C. BilbaoView author...