Biology subjects

Neumann, C. K. A.

Publications and source records attributed to Neumann, C. K. A..

3 recordsLinked to original sources

bioRxiv2020

Cancer Stem Cell Enrichment and Metabolic Substrate Adaptability are Driven by Hydrogen Sulfide Suppression in Glioblastoma

Glioblastoma (GBM) remains among the deadliest of human malignancies. The emergence of the cancer stem cell (CSC) phenotype represents a major challenge to disease management and durable treatment response. The extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. The CSC state endows cells with a fluid metabolic profile, enabling the utilization of multiple nutrient sources. Therefore, to test the impact of diet on CSC enrichment, we evaluated disease progression in tumor-bearing mice fed an obesity-inducing high-fat diet (HFD) versus an energy-balanced, low-fat control diet. HFD consumption resulted in hyper-aggressive disease that was accompanied by CSC enrichment and shortened survival. HFD consumption also drove intracerebral accumulation of saturated fats, which in turn inhibited the production and signaling of the gasotransmitter hydrogen sulfide (H2S). H2S is an endogenously produced bio-active metabolite derived from sulfur amino acid catabolism. It functions principally through protein S-sulfhydration and regulates a variety of programs including mitochondrial bioenergetics and cellular metabolism. Inhibition of H2S synthesis resulted in increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to cytotoxicity and death of cultured GBM cells. Compared to non-cancerous controls, patient GBM specimens were reduced in overall protein S-sulfhydration, which was primarily lost from proteins regulating cellular metabolism. These findings support the hypothesis that diet-regulated H2S signaling serves to suppress GBM by restricting metabolic adaptability, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients. One Sentence SummaryConsumption of a high-fat diet (HFD) accelerates glioblastoma (GBM) by inhibiting the production and signaling of the tumor-suppressive metabolite hydrogen sulfide (H2S).

cancer biology↗

bioRxiv2020

Membrane-Bound O-Acyltransferase 7 (MBOAT7) is a Key Regulator of Glycolysis in Clear Cell Renal Carcinoma.

ObjectiveThe most common and deadliest urological cancer is clear cell Renal Cell Carcinoma (ccRCC). ccRCC is characterized by striking reorganization of both carbohydrate and lipid metabolism. It was recently demonstrated that lipid remodeling enzyme Membrane-Bound O-Acyltransferase 7 (MBOAT7) that generates phosphatidylinositol (PI) is important for the ccRCC progression. However, whether MBOAT7-driven PI remodeling is associated with other metabolic alterations commonly found in ccRCC is poorly understood. MethodsMBOAT7 deficient ccRCC cell lines were generated by genome editing, and were characterized by a general reduction in glycolytic capactiy. Using targeted metabolomics approach in Caki-1 cells, we measured the glycolytic intermediates and the relative expression of key glycolytic enzymes. We also measured basal respiration and maximal respiration with MBOAT7 deficiency in the presence of glucose. Lastly, in vivo xenograft studies were performed with parental and MBOAT7 deficient cells. ResultsMBOAT7 deficiency was associated with a reduction in glycolytic gene expression and protein abundance. In parallel, we found that glycolytic intermediates similarly decreased which may contribute to a reduction in glycolysis. MBOAT7 deficiency reduces basal respiration and maximal respiration. Similarly, we see maximum glycolytic capacity also reduced with MBOAT7 loss of function. Finally, the in vivo xenograft demonstrated MBOAT7 knockout significantly increased overall survival and reduced glycolytic HK2 protein abundance in vivo. ConclusionsOur work highlights MBOAT7 as a key regulator of glycolysis in ccRCC. Our data provides additional evidence that suggests MBOAT7 as a novel target to regulate tumor growth in vivo.

cancer biology↗

bioRxiv2019

MBOAT7-Driven Phosphatidylinositol Remodeling Promotes the Progression of Clear Cell Renal Cell Carcinoma.

The most common kidney cancer, clear cell Renal Cell Carcinoma (ccRCC) is closely associated with obesity. In fact, the \"clear cell\" variant of RCC is given this name due to large lipid droplets within the tumor cells. Although it is well appreciated that renal lipid metabolism is altered in ccRCC, the mechanisms driving this are not well understood. Leveraging a shotgun lipidomics approach we have identified a lipid signature for ccRCC that includes an increase in arachidonic acid-enriched phosphatidylinositols (AA-PI). In parallel, we found that ccRCC tumors have increased expression of the acyltransferase enzyme membrane bound O-acyltransferase domain containing 7 (MBOAT7) that contributes to AA-PI synthesis. In ccRCC patients, MBOAT7 expression increases with tumor grade, and increased MBOAT7 expression correlates with poor survival. Genetic deletion of MBOAT7 in ccRCC cells decreases proliferation and induces cell cycle arrest, and MBOAT7-/- cells fail to form tumors in vivo. RNAseq of MBOAT7-/- cells identified alterations in cell migration and extracellular matrix organization, which were functionally validated in migration assays. Our work highlights the accumulation of AA-PI in ccRCC and demonstrate a novel way to decrease the AA-PI pool in ccRCC by limiting MBOAT7. Our data reveal that metastatic ccRCC is associated with altered AA-PI metabolism, and identify MBOAT7 as a novel target in advanced ccRCC.

cancer biology↗