Severe consequences of a high-lipid diet include hydrogen sulfide dysfunction and enhanced aggression in glioblastoma
Daniel J. Silver, … , Christopher Hine, Justin D. Lathia
Daniel J. Silver, … , Christopher Hine, Justin D. Lathia
Published July 13, 2021
Citation Information: J Clin Invest. 2021;131(17):e138276. https://doi.org/10.1172/JCI138276.
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Research Article Oncology Stem cells

Severe consequences of a high-lipid diet include hydrogen sulfide dysfunction and enhanced aggression in glioblastoma

Abstract

Glioblastoma (GBM) remains among the deadliest of human malignancies, and the emergence of the cancer stem cell (CSC) phenotype represents a major challenge to durable treatment response. Because the environmental and lifestyle factors that impact CSC populations are not clear, we sought to understand the consequences of diet on CSC enrichment. We evaluated disease progression in mice fed an obesity-inducing high-fat diet (HFD) versus a low-fat, control diet. HFD resulted in hyperaggressive disease accompanied by CSC enrichment and shortened survival. HFD drove intracerebral accumulation of saturated fats, which inhibited the production of the cysteine metabolite and gasotransmitter, hydrogen sulfide (H2S). H2S functions principally through protein S-sulfhydration and regulates multiple programs, including bioenergetics and metabolism. Inhibition of H2S increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to death of cultured GBM cells and stasis of GBM tumors in vivo. Syngeneic GBM models and GBM patient specimens present an overall reduction in protein S-sulfhydration, primarily associated with proteins regulating cellular metabolism. These findings provide clear evidence that diet-modifiable H2S signaling serves to suppress GBM by restricting metabolic fitness, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for patients with GBM.

Authors

Daniel J. Silver, Gustavo A. Roversi, Nazmin Bithi, Sabrina Z. Wang, Katie M. Troike, Chase K.A. Neumann, Grace K. Ahuja, Ofer Reizes, J. Mark Brown, Christopher Hine, Justin D. Lathia

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Figure 1

High-fat diet consumption drives CSC enrichment and accelerates glioblastoma progression.

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High-fat diet consumption drives CSC enrichment and accelerates glioblas...
(A) In vivo experimental design employed to test whether HFD consumption modifies GBM progression. (B–D) For the syngeneic GBM models CT2A and GL261, as well as the patient-derived GBM model hGBM 23, Kaplan-Meier survival analysis confirmed significant truncation of overall survival under conditions of HFD consumption compared with consumption of control diets. P values determined by log-rank survival analysis and experimental group (n) size noted above. (E–G) In vivo limiting dilution analysis was performed for the 3 syngeneic GBM models CT2A, GL261, and KR158. For each model, tumors were initiated using 50,000, 20,000, 15,000, 10,000, and 5000 cells per animal. P values were determined using the Walter and Eliza Hall ELDA portal (60) comparing the total number of endpoint animals in the HFD group versus the control diet group at the conclusion of each set of experiments. (H and I) Representative immunofluorescence micrographs of the CSC population observed in the GBM tumor microenvironment under HFD- versus chow-fed conditions. Scale bars: 75 μm. The CSC-associated transcription factor SOX2 was visualized in red; MCM2, visualized in green, identified the bulk tumor cell population; and nuclei were visualized in blue using DAPI. (J) SOX2 fluorescence intensity, normalized to the MCM2 fluorescence intensity, allowed us to measure CSC enrichment within the tumor microenvironment. Each dot represents the fluorescence intensity of the SOX2 signal divided by the fluorescence intensity of the MCM2 signal for each image. P value determined by unpaired t test.