Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males
Tao Sun, Nicole M. Warrington, Jingqin Luo, Michael D. Brooks, Sonika Dahiya, Steven C. Snyder, Rajarshi Sengupta, Joshua B. Rubin
Tao Sun, Nicole M. Warrington, Jingqin Luo, Michael D. Brooks, Sonika Dahiya, Steven C. Snyder, Rajarshi Sengupta, Joshua B. Rubin
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Research Article Oncology

Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males

Abstract

The prevalence of brain tumors in males is common but unexplained. While sex differences in disease are typically mediated through acute sex hormone actions, sex-specific differences in brain tumor rates are comparable at all ages, suggesting that factors other than sex hormones underlie this discrepancy. We found that mesenchymal glioblastoma (Mes-GBM) affects more males as the result of cell-intrinsic sexual dimorphism in astrocyte transformation. We used astrocytes from neurofibromin-deficient (Nf1–/–) mice expressing a dominant-negative form of the tumor suppressor p53 (DNp53) and treated them with EGF as a Mes-GBM model. Male Mes-GBM astrocytes exhibited greater growth and colony formation compared with female Mes-GBM astrocytes. Moreover, male Mes-GBM astrocytes underwent greater tumorigenesis in vivo, regardless of recipient mouse sex. Male Mes-GBM astrocytes exhibited greater inactivation of the tumor suppressor RB, higher proliferation rates, and greater induction of a clonogenic, stem-like cell population compared with female Mes-GBM astrocytes. Furthermore, complete inactivation of RB and p53 in Mes-GBM astrocytes resulted in equivalent male and female tumorigenic transformation, indicating that intrinsic differences in RB activation are responsible for the predominance of tumorigenic transformation in male astrocytes. Together, these results indicate that cell-intrinsic sex differences in RB regulation and stem-like cell function may underlie the predominance of GBM in males.

Authors

Tao Sun, Nicole M. Warrington, Jingqin Luo, Michael D. Brooks, Sonika Dahiya, Steven C. Snyder, Rajarshi Sengupta, Joshua B. Rubin

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Figure 3

Male predominant in vivo tumorigenesis occurs irrespective of recipient mouse sex.

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Male predominant in vivo tumorigenesis occurs irrespective of recipient ...
(A) Intracranial implantation of EGF-treated male (n = 22) and female (n = 22) Nf1–/– DNp53 astrocytes from 3 independent litters resulted in death of 100% of mice receiving male cell implants and 36% of mice receiving female cell implants (***P < 0.0001, log-rank test). (B) Intracranial tumors were recognizable in situ by their EGFP expression (asterisk). (C) Intracranial tumors exhibited features of GBM, including nuclear pleomorphism and pseudopalisading necrosis (asterisk, top row), GFAP positivity, and abundant mitoses (asterisk, bottom row). Scale bar: 20 microns. (D) Male (black arrows) and female (white arrows) EGF-treated Nf1–/– DNp53 astrocytes were implanted into the flanks of male and female mice. Male cells gave rise to more tumors regardless of the recipient mouse sex. (E) Flank tumor volumes measured by calipers at 6 weeks. Each symbol represents an individual tumor. Mean volumes were significantly different (**P = 0.001, Wilcoxon rank test).