ORCID
http://orcid.org/0000-0002-6566-3986
Date of Award
Spring 5-15-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Nearly all complex human diseases exhibit some degree of sex difference in incidence, age of onset, disease severity, and/or response to treatment. Sex differences are observed in a wide range of nervous system disorders, including neurodevelopmental disorders, psychiatric diseases, neuroimmunological disorders, neurodegenerative diseases, and central nervous system (CNS) tumors. Males have increased incidence rates for most CNS tumor types. Sex differences in brain tumor incidence rates are observed in studies from around the world, across a wide range of cultures, in both pediatric and adult populations, and even extend to other species. Males also have decreased survival from brain tumors, both when comparing all brain tumors combined, and when looking specifically at the most common brain tumor types in both children and adults. The persistence of the male predominance in brain tumors across cultures, ages, and species strongly suggests that the sex differences observed stem from a biologic origin, rather than behavioral differences between men and women. While hormones can play a mechanistic role for some tumor histologies, the observation that sex differences in tumor incidence and outcome are present throughout the lifespan, even though hormone levels vary widely from childhood to old age, and are also observed in neutered and spayed dogs, clearly indicates a role for hormone-independent mechanisms. The male and female differences that underlie these mechanisms are established through sexual differentiation, the biological process by which males and females diverge physiologically from the undifferentiated zygote. Sexual differentiation begins at fertilization and continues throughout the lifespan; it involves genetic, epigenetic, metabolic, and hormonal mechanisms, and impacts virtually every body system. Since sex differences can be encoded at the genetic, cellular, tissue, and systemic level, investigating how sex influences health and disease requires a multi-scale approach. This work will describe three main projects, which together explore how male and female differences across these different scales contribute to sex differences in brain tumor risks and outcomes. The first project described will focus on the genetic/epigenetic scale, showing that male and female glioblastoma cells differ in the distribution of Brd4-bound active enhancers, which results in different transcriptional states and opposing effects of epigenetic drugs targeting Brd4. The second project will focus on the cellular scale; it shows that female glioblastoma cells are more sensitive to p21-induced cellular senescence following irradiation, and that sex differences in p21 sensitivity are patterned by exposure to gonadal hormones in utero. The third project will focus on the tissue scale, showing that brain tumors from women with previous pregnancies contain fetal microchimeric cells within the tumor microenvironment, a phenomenon unique to women, with potential implications for immune regulation and immunotherapy. As a whole, this body of work demonstrates how sex differences in brain tumor biology are encoded at every level, from the genetic scale to the systemic scale. As we move towards more personalized medicine approaches to treatment, it will be critical to incorporate sex in the design of clinical trials and in the implementation of therapies in clinical practice if we are to maximize treatment success for all patients, male and female.
Language
English (en)
Chair and Committee
Joshua Rubin
Committee Members
Milan Chheda, Joseph Dougherty, Harrison Gabel, Kristen Kroll,
Recommended Citation
Broestl, Lauren, "Multi-Scalar Contributions to Sex Differences in Brain Tumor Incidence and Outcome" (2023). Arts & Sciences Electronic Theses and Dissertations. 2835.
https://openscholarship.wustl.edu/art_sci_etds/2835