Date of Award

Spring 5-15-2022

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Many human diseases show sex differences in incidence, age of onset, and outcome, including autoimmune diseases, neurological diseases, psychiatric disorders, cardiovascular diseases, metabolic diseases, neurodevelopmental disorders, and cancer. For most cancers, incidence and mortality rates are higher in males. Lung and brain cancers are no exception. Overall, lung cancer is more common in males. Furthermore, mortality rates of non-small cell lung cancer (NSCLC), the most common subtype of lung cancer, are significantly higher in males. The underlying reasons for sex differences in NSCLC mortality rates are largely unknown. Most brain cancers are also more common in males. The male prevalence persists across all age groups and all geographical regions, indicating that these sex differences are not solely driven by environmental factors or circulating sex hormones. Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, exhibits a male to female ratio of 1.6 to 1. Furthermore, female GBM patients have a survival advantage. The biological mechanisms contributing to these sex differences remain unknown. Sex differences in cancer incidence are likely driven by various cellular mechanisms involved in cancer development, such as proliferation, interactions with the immune system, angiogenesis, cell migration, genome instability, and metabolism. Sex differences in cancer survival are likely to involve these mechanisms as well as those that govern treatment response. This dissertation explored sex differences in cancer metabolism and treatment responses in GBM and NSCLC. We show that male and female GBM surgical specimens exhibit considerable sex differences in amino acid metabolite abundance, including glutamine and branched-chain amino acid (BCAA) metabolites. In addition, we show that glutamine uptake is greater in male glioma patients and male murine transformed astrocytes (Nf1-/-; DNp53 astrocytes). Furthermore, we found increased glutamine utilization and glutaminase 1 (GLS1) expression in male transformed astrocytes. Concordantly, GLS1 inhibition leads to greater growth reduction in male transformed astrocytes. The sensitivity to GLS1 inhibition in males is driven by their dependence on glutamine-derived glutamate to replenish their TCA cycle. Female growth is glutamine-independent because of their greater pyruvate carboxylase-mediated TCA cycle replenishment. These findings indicate that male GBM are more dependent on glutamine to maintain proliferation. Metabolite analysis of male and female GBM surgical specimens also showed that BCAA metabolites are more abundant in male GBM. The BCAA leucine stimulates the mTOR pathway, an important regulator of metabolism, growth, and protein biosynthesis. We found that male transformed astrocytes show a greater change in mTOR pathway activity upon serum starvation and pathway stimulation. Furthermore, high phosphorylation levels of mTOR, an indicator for pathway activation, are associated with poor survival in male, but not female, GBM patients. Thus, sex differences in mTOR pathway activity may lead to sex differences in metabolism and vice versa. We also investigated the molecular mechanisms underlying sex differences in other GBM treatment responses. We found that female transformed astrocytes are more sensitive to radiation than male cells. This sex difference in cytotoxicity was driven by a greater induction of senescence in female transformed astrocytes. Furthermore, we identified the CDK inhibitor p21 as a likely mediator of the sex differences in senescence induction. Last, we show that gonadal sex, rather than chromosomal sex, underlie sex differences in p21-mediates senescence response. These findings suggest that sex differences in the senescence response to radiation may contribute to sex differences in treatment response in GBM patients. Last, using publicly available [13C6]glucose tracing data in over 80 NSCLC cell lines, we found that male cells generate significantly more serine from glucose. Furthermore, de novo serine biosynthesis was correlated with antifolate sensitivity in male cells only. Patient mRNA expression data showed that enzymes involved in de novo serine biosynthesis and the folate cycle are higher expressed in male lung and pan-cancer patient samples. Additionally, high serine synthesis gene expression was associated with antifolate sensitivity in male, but not female, patient-derived pan-cancer cell lines. These findings indicate that de novo serine biosynthesis is a reliable marker for antifolate sensitivity in male NSCLC in vitro cultures. In summary, these data show that sex differences in metabolism persist in GBM and NSCLC and that these sex differences may be utilized to develop and improve treatment approaches to enhance outcome for both, male and female cancer patients.


English (en)

Chair and Committee

Joshua B. Rubin

Committee Members

Joseph E. Ippolito


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