Abstract

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 with 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.

中文翻译：

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JAM-A 在胶质母细胞瘤中充当女性小胶质细胞肿瘤抑制因子。

 抽象的

 背景

胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤，预后不佳。此前，我们发现连接粘附分子 A (JAM-A)（一种细胞粘附分子）在人 GBM 癌症干细胞中高度升高，可预测患者预后不良。虽然 JAM-A 在肿瘤微环境中的其他细胞（特别是小胶质细胞和巨噬细胞）中也高度表达，但这些细胞中的 JAM-A 表达如何影响肿瘤生长尚未确定。本研究的目的是了解微环境 JAM-A 在介导 GBM 生长中的作用。

 方法

将同源神经胶质瘤细胞系 GL261 和 SB28 颅内移植到雄性和雌性野生型 (WT) 和 JAM-A 缺陷小鼠中，并评估肿瘤和体外存活和小胶质细胞活化的差异。进行RNA测序以确定所有基因型之间差异调节的基因，并在体外和体内验证差异。

 结果

我们发现，与 WT 雌性小鼠以及 JAM-A 缺陷型和雄性 WT 小鼠相比，JAM-A 缺陷型雌性小鼠死于 GBM 的速度更快。对肿瘤中小胶质细胞的分析表明，JAM-A 缺陷的雌性小胶质细胞更加活跃，RNA 测序发现Fizz1和Ifi202b的表达升高，特别是在 JAM-A 缺陷的雌性小胶质细胞中。

 结论

我们的研究结果表明，JAM-A 的功能是抑制女性肿瘤微环境中的致病性小胶质细胞激活，强调了 GBM 微环境中性别差异的新兴作用，并表明性别差异超出了先前报道的肿瘤细胞内在差异。