The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma.
Marla E TharpClaudia Z HanChristopher BalakConor FitzpatrickCarolyn O'ConnorSebastian PreisslJustin BuchananAlexi NottLaure EscoubetKonstantinos MavrommatisMihir GuptaMarc S SchwartzU Hoi SangPamela S JonesMichael L LevyDavid D GondaSharona Ben-HaimJoseph CiacciDavid BarbaAlexander KhalessiNicole G CoufalClark C ChenChristopher K GlassDavid C PagePublished in: bioRxiv : the preprint server for biology (2024)
Biological sex is an important risk factor in cancer, but the underlying cell types and mechanisms remain obscure. Since tumor development is regulated by the immune system, we hypothesize that sex-biased immune interactions underpin sex differences in cancer. The male-biased glioblastoma multiforme (GBM) is an aggressive and treatment-refractory tumor in urgent need of more innovative approaches, such as considering sex differences, to improve outcomes. GBM arises in the specialized brain immune environment dominated by microglia, so we explored sex differences in this immune cell type. We isolated adult human TAM-MGs (tumor-associated macrophages enriched for microglia) and control microglia and found sex-biased inflammatory signatures in GBM and lower-grade tumors associated with pro-tumorigenic activity in males and anti-tumorigenic activity in females. We demonstrated that genes expressed or modulated by the inactive X chromosome facilitate this bias. Together, our results implicate TAM-MGs, specifically their sex chromosomes, as drivers of male bias in GBM.
Keyphrases
- inflammatory response
- endothelial cells
- neuropathic pain
- papillary thyroid
- squamous cell
- genome wide
- induced pluripotent stem cells
- risk factors
- childhood cancer
- lipopolysaccharide induced
- stem cells
- single cell
- palliative care
- type diabetes
- squamous cell carcinoma
- cell therapy
- lymph node metastasis
- dna methylation
- gene expression
- resting state
- weight loss
- transcription factor
- skeletal muscle
- brain injury
- insulin resistance
- white matter
- anti inflammatory
- genome wide identification
- smoking cessation