Project 1: Sex-specific developmental epigenetics in gliomagenesis

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PROJECT SUMMARY Glioblastoma (GBM) is the most devastating form of brain cancer. In the next year, approximately 22,000 Americans will develop GBM and nearly the same number will die from it. While GBM occurs in both males and females, we can reliably predict that of the 22,000 new cases, 8,500 will be in females while the remaining 13,500 cases will be in males. Moreover, while the median survival for female GBM patients next year is expected to be approximately 22 months, for males it will be closer to 16 months. The molecular bases for these consistent and significant sex differences in incidence and survival are unexplained. In the absence of an explanation, it is impossible to fully know what the implications are for modeling GBM in the laboratory and for treating GBM in the clinic. Defining the genetic and epigenetic mechanisms that underlie sex differences in GBM incidence and survival is the focus of this project. We recently published an analysis of GBM patient imaging, transcriptomes, and survival in which we determined that female GBM patients exhibit greater response to the current standard treatments and that their survival is highly correlated with expression of components of the integrin signaling pathway. In contrast, male GBM patients exhibit less robust response to current treatment and their survival appears to be more potently determined by expression levels of the cell cycle regulatory machinery. These data not only provide new insights into sex differences in GBM biology, they suggest that sex-specific targeting of pathways that support survival in females and males could lead to improved outcomes for all patients. Sex differences in health and disease accrue throughout life as a consequence of sexual differentiation. Sexual differentiation, which begins at the time of fertilization, involves genetic and epigenetic mechanisms, as well as the acute actions of circulating sex hormones. We have developed murine models for studying sex differences in GBM. Here, we will use our innovative Cas-9 adaptation of the established four-core genotypes model for measuring the distinct contributions of sex chromosome complement and gonadal secretions to sex differences in GBM biology. Coupled with in utero electroporation of gRNAs and other genetic constructs, we will be uniquely positioned to assess how sex-specific changes in chromatin structure and expression of specific genes mediate the sex differences in GBM. We have two aims to address the hypothesis that sex differences in GBM incidence and outcome are determined at early stages of in utero sexual differentiation (Aim 1) and involve sex-specific patterning in gene expression and activity in integrin and cell cycle regulatory pathways (Aim 2). At all stages of this work we will incorporate specific questions about sexual differentiation and iron metabolism (Project 2) and microglia function (Project 3). Together these studies will provide critical information in our effort to understand the molecular basis for sex differences in GBM and a path for the implementation of sex-specific treatment for GBM and other cancers that exhibit sex differences in incidence and outcome.