Sex-specific gene and pathway modeling of inherited glioma risk

Ostrom, Quinn T.; Coleman, Warren; Huang, William; Rubin, Joshua B.; Lathia, Justin D.; Berens, Michael E.; Speyer, Gil; Liao, Peter; Wrensch, Margaret; Eckel‐Passow, Jeanette E.; Armstrong, Georgina; Rice, Terri; Wiencke, John K.; McCoy, Lucie; Hansen, Helen M.; Amos, Christopher I.; Bernstein, Jonine L.; Claus, Elizabeth B.; Il’yasova, Dora; Johansen, Christoffer; Lachance, Daniel H.; Lai, Rose; Merrell, Ryan; Sadetzki, Siegel; Schildkraut, Joellen M.; Shete, Sanjay; Houlston, Richard S.; Jenkins, Robert B.; Andersson, Ulrika; Rajaraman, Preetha; Chanock, Stephen J.; Linet, Martha S.; Wang, Zhaoming; Yeager, Meredith; Melin, Beatrice; Bondy, Melissa L.; Barnholtz‐Sloan, Jill S.

doi:10.1101/235408

Cited by 5 publications

(5 citation statements)

References 47 publications

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“…Furthermore, these differences manifest clinically, with females showing a more dispersive phenotype radiographically (Yang et al, 2019) and males experiencing a poorer prognosis . There is supporting evidence in the literature suggesting that sexual dimorphism in GBM is mediated through sexspecific differences in tumor cell-intrinsic oncogenic signaling pathways (Kfoury et al, 2018;Ostrom et al, 2019;Ostrom and Kinnersley, 2018;Sun et al, 2014), epigenetic states, and metabolic profiles (Ippolito et al, 2017). While sex differences might induce differential GBM cellintrinsic responses, leading to differences in survival, sex-specific differences in the tumor microenvironment have not yet been elucidated.…”

Section: Introductionmentioning

confidence: 97%

JAM-A functions as a female microglial tumor suppressor in glioblastoma

et al. 2020

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Background Glioblastoma (GBM) is the most aggressive primary brain tumor and has a dismal prognosis. Previously, we identified that junctional adhesion molecule-A (JAM-A), a cell adhesion molecule, is highly elevated in human GBM cancer stem cells and predicts poor patient prognosis. While JAM-A is also highly expressed in other cells in the tumor microenvironment, specifically microglia and macrophages, how JAM-A expression in these cells affects tumor growth has yet to be determined. The goal of this study was to understand the role of microenvironmental JAM-A in mediating GBM growth. Methods Male and female wild-type (WT) and JAM-A-deficient mice were transplanted intracranially with the syngeneic glioma cell lines GL261 and SB28 and were assessed for differences in survival and microglial activation in tumors and in vitro. RNA-sequencing was performed to identify differentially regulated genes among all genotypes, and differences were validated in vitro and in vivo. Results We found that JAM-A-deficient female mice succumbed to GBM more quickly compared to WT females and JAM-A-deficient and male WT mice. Analysis of microglia in the tumors revealed that female JAM-A-deficient microglia were more activated, and RNA-sequencing identified elevated expression of Fizz1 and Ifi202b specifically in JAM-A-deficient female microglia. Conclusions Our findings suggest that JAM-A functions to suppress pathogenic microglial activation in the female tumor microenvironment, highlighting an emerging role for sex differences in the GBM microenvironment and suggesting that sex differences extend beyond previously reported tumor cell-intrinsic differences.

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Section: Introductionmentioning

confidence: 97%

JAM-A functions as a female microglial tumor suppressor in glioblastoma

et al. 2020

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“…A GWAS from 2018 showed that rs11979158 carries a risk only for males and rs55705857 is more strongly associated in females (58). A study published recently revealed that female-specific association can be found for some TERT variants and malespecific associations are found for certain EGFR variants (59).…”

Section: Molecular Differencesmentioning

confidence: 99%

Biomarkers In Brain Tumors With Focus On Glioblastoma

Łysiak

2022

Linköping University Medical Dissertations

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“…Current treatments consist of chemotherapy, radiation, and the median survival is ~15 months [2,3] . Many factors can affect glioblastoma prognosis, including diagnosis stage, molecular and genetic features of the tumor, age, and sex [4,5] . Estrogens are well known to be neuroprotective in a variety of central nervous system disorders, including Alzheimer's disease [6] , Parkinson's disease [7] , and ischemic injury caused by stroke [8] .…”

Section: Introductionmentioning

confidence: 99%

Estrogen Receptor Variant ER-α36 Facilitates Estrogen Signaling Via EGFR Signaling in Glioblastoma

Wang

et al. 2022

Preprint

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Glioblastoma is a deadly and common primary brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity. Sex differences may play a role in patient outcome. Previous studies showed that ER-α36, a variant of the estrogen receptor, mediated non-genomic estrogen signaling and is highly expressed in many ER-negative tumors. ER-α36 also associates with the EGFR. We showed that ER-α36 was highly expressed and confirmed that ER-α36 co-labels with EGFR in glioma specimens. We also investigated the mechanisms of estrogen induced proliferation in ER-α-negative cells U87 and U251. We found that glioblastoma cell varying responsive to mitogenic estrogen signaling which correlated with ER-α36 expression, and knockdown of ER-α36 diminished the response. Exposure to estrogen also caused up-regulation of cyclin protein expression in vitro. We also found that low concentrations of estrogen promoted SRC-Y-416 and inhibited SRC-Y-527 phosphorylation, corresponding with activated SRC signaling. Inhibiting SRC or EGFR abolished estrogen-induced mitogenic signaling, including cyclin expression and MAPK phosphorylation. Cumulatively, our results demonstrate that ER-α36 promotes non-genomic estrogen signaling via the EGFR/SRC/MAPK pathway in glioblastoma. This may be important for the treatment of ER-α-negative glioblastomas that retain high level of ER-α36, since estrogen may be a viable therapeutic target for these patients.

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Sex-specific gene and pathway modeling of inherited glioma risk

Cited by 5 publications

References 47 publications

JAM-A functions as a female microglial tumor suppressor in glioblastoma

JAM-A functions as a female microglial tumor suppressor in glioblastoma

Biomarkers In Brain Tumors With Focus On Glioblastoma

Estrogen Receptor Variant ER-α36 Facilitates Estrogen Signaling Via EGFR Signaling in Glioblastoma

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