Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment

Sponagel, Jasmin; Jones, Jill K.; Frankfater, Cheryl; Zhang, Shanshan; Tung, Olivia; Cho, Kevin; Tinkum, Kelsey L.; Gass, Hannah; Nunez, Elena; Spitz, Douglas R.; Chinnaiyan, Prakash; Schaefer, Jacob; Patti, Gary J.; Graham, Maya Srikanth; Mauguen, Audrey; Grkovski, Milan; Dunphy, Mark; Krebs, Simone; Luo, Jingqin; Rubin, Joshua B.; Ippolito, Joseph E.

doi:10.1016/j.medj.2022.08.005

Cited by 19 publications

(14 citation statements)

References 71 publications

(102 reference statements)

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“…An accompanying analysis of survival data from 3.7 million cases in the SEER database, representing approximately 28% of the cancer population, confirmed that mortality rates are higher for males compared to females [2]. These clinically important sex differences are concordant with described sex differences in cell biology including, response to genotoxic stress [3,4], DNA repair [5,6], mutational burden [7,8], metabolism [9,10], and cell cycle regulation [11][12][13], as well as in systems biology including: immunity [14], metabolism [15,16], tissue repair [17,18], and longevity [19,20]. This suggests that therapies for all cancer patients may be advanced by a realistic translation of sex differences into clinical practice.…”

Section: Introductionmentioning

confidence: 64%

Accounting for sex differences variability in the design of sex-adapted cancer treatments

Yang

Rubin

2023

Preprint

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The significant sex differences that exist in cancer mechanisms, incidence, and survival, have yet to impact clinical practice. We hypothesized that one barrier to translation is that sex differences in cancer phenotypes resemble sex differences in height: highly overlapping, but distinct, male and female population distributions that vary continuously between female- and male- biased extremes. A consequence of this variance is that sex-specific treatments are rendered unrealistic, and our translational goal should be adaptation of treatment to the unique mix of sex-biased mechanisms that are present in each patient. To develop a tool that could advance this goal, we applied a Bayesian Nearest Neighbor (BNN) analysis to 8370 cancer transcriptomes from 26 different adult and 4 different pediatric cancer types to establish patient-specific Transcriptomic Sex Indices (TSI). TSI precisely partitions an individual patients whole transcriptome into female- and male- biased components such that cancer type, patient sex, and transcriptomics, provide a novel and patient-specific mechanistic identifier that can be used for sex-adapted, precision cancer treatment planning.

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Section: Introductionmentioning

confidence: 64%

Accounting for sex differences variability in the design of sex-adapted cancer treatments

Yang

Rubin

2023

Preprint

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“…Specifically, the stable isotope-labeled nutrient analyzed in this study was [ 13 C 6 ] glucose and its analyses were restricted to serine, glycine, and selected glycolytic and TCA cycle metabolites. Emerging data from our group also showed sex differences in anaplerosis from glutamine in GBM and that these sex differences may not come from carbons as part of the TCA cycle, but rather nitrogens for transamination and amino acid synthesis ( Sponagel et al., 2022 ). Therefore, follow-up studies would need to be performed to confirm whether similar sex differences exist in NSCLC.…”

Section: Discussionmentioning

confidence: 88%

“…Here, we provide evidence that established cancer cell lines exhibit sex differences in metabolism even after years of in vitro culture. In addition to sex differences in de novo serine biosynthesis in NSCLC cell lines, we recently reported that glioma cell lines exhibit sex differences in glutaminase 1 expression ( Sponagel et al., 2022 ), suggesting that sex differences in cancer cell lines persist across multiple metabolic pathways. Not only do these findings underline the importance of correctly identifying and considering the sex of cancer cell lines in the laboratory setting but it also identifies a completely unexplored and very important scientific space.…”

Section: Discussionmentioning

confidence: 99%

De novo serine biosynthesis from glucose predicts sex-specific response to antifolates in non-small cell lung cancer cell lines

Sponagel¹,

Devarakonda²,

Rubin³

et al. 2022

iScience

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“…Further, AR signaling increased glutamine metabolism and utilization in gliomas (Sponagel et al, 2022). However, these studies have focused on cancer cells, which can have dysregulation of normal metabolic patterns and dysregulation of sex hormone receptor expression.…”

Section: Introductionmentioning

confidence: 99%

“…Prior research on sex hormone signaling and cell metabolism has shown in cancer that androgens signaling through the AR dysregulate glycolysis, the citric acid cycle, amino acid metabolism, and fatty acid metabolism through transcriptional, epigenetic, and co-receptor changes in prostate cancer cells (Barfeld et al, 2014; Massie et al, 2011; Uo et al, 2020). Further, AR signaling increased glutamine metabolism and utilization in gliomas (Sponagel et al, 2022). However, these studies have focused on cancer cells, which can have dysregulation of normal metabolic patterns and dysregulation of sex hormone receptor expression.…”

Section: Introductionmentioning

confidence: 99%

Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

Chowdhury¹,

Cephus²,

Madden³

et al. 2023

Preprint

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Females have increased prevalence of many Th17-mediated diseases. While androgen signaling decreases Th17-mediated inflammation, the mechanisms are not fully understood. Th17 cells rely on glutaminolysis; however, it remains unclear whether androgen receptor (AR) signaling in males modifies glutamine metabolism to suppress Th17-mediated inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis. Using allergen-induced airway inflammation models, we determined females, but not males, had a critical reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake by reducing expression of glutamine transporters. These findings were confirmed in circulating human Th17 cells with minimal reliance on glutamine uptake in male compared to female Th17 cells. We found that AR signaling attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for design and implementation of Th17 or glutaminolysis targeted therapeutics.

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Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment

Cited by 19 publications

References 71 publications

Accounting for sex differences variability in the design of sex-adapted cancer treatments

Accounting for sex differences variability in the design of sex-adapted cancer treatments

De novo serine biosynthesis from glucose predicts sex-specific response to antifolates in non-small cell lung cancer cell lines

Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

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