Biology subjects

Sponagel, J.

Publications and source records attributed to Sponagel, J..

3 recordsLinked to original sources

bioRxiv2021

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

Lung cancer is the leading cause of cancer-related death. Intriguingly, males with non-small cell lung cancer (NSCLC), the most common type of lung cancer, have a higher mortality rate than females. Here, we investigated the role of serine metabolism as a predictive marker for sensitivity to the antifolate pemetrexed in male and female NSCLC cell lines. Using [13C6] glucose tracing in NSCLC cell lines, we found that male cells generated significantly more serine from glucose than female cells. Higher serine biosynthesis was further correlated with increased sensitivity to pemetrexed in male cells only. Concordant sex differences in metabolic gene expression were evident in NSCLC and pan-cancer transcriptome datasets, suggesting a potential mechanism with wide-reaching applicability. These data were further validated by integrating antifolate drug cytotoxicity and metabolic pathway transcriptome data from pan-cancer cell lines. Together, these findings highlight the importance of considering sex differences in cancer metabolism to improve treatment for all patients.

cancer biology↗

bioRxiv2021

Sex Differences in Brain Tumor Glutamine Metabolism Reveal Sex-Specific Vulnerabilities to Treatment

Sex differences in normal metabolism are well described, but whether they persist in cancerous tissue is unknown. We assessed metabolite abundance in glioblastoma surgical specimens and found that male glioblastomas are enriched for amino acids, including glutamine. Using PET imaging, we found that gliomas in male patients exhibit significantly higher glutamine uptake. These sex differences were well-modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for -ketoglutarate synthesis and TCA cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase-mediated TCA cycle replenishment. Thus, clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism is an opportunity to improve treatments for all patients through further laboratory and clinical research.

cancer biology↗

bioRxiv2021

Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in both wildtype and transformed murine astrocytes and patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned by gonadal sex. These data suggest that sex differences in p21 induced senescence contribute to the female survival advantage in GBM.

cancer biology↗