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Single-cell atlas of the leiomyoma microenvironment reveals hallmarks of myometrial vascular inflammation

ABSTRACT: Uterine fibroids or leiomyoma are benign smooth muscle-derived tumours and are the most common pelvic uterine tumours of women in reproductive age. Large numbers of patients present with symptoms of heavy or prolonged menstrual bleeding, dyspareunia, pelvic pain, miscarriage, and infertility. The underlying causes are not understood; however it is hypothesized that fibroid-uterine interactions orchestrate clinical sequelae, mediated through the pseudocapsule, an anatomical entity that surrounds the myoma and separates it from normal myometrium. We here present a single cell atlas of the uterine pseudocapsule architecture by integrating single nuclei transcriptomics with highly multiplexed immunofluorescence imaging. The data suggest vascular inflammation leading to substantial infiltration of activated innate and adaptive immune cells in the pseudocapsule and we map fibroblast/stromal and endothelial cell activation states and interactions. The results advance our understanding of molecular events underlying leiomyoma pathology and provide novel insights into aberrant and actionable immunological processes occurring in the tumour microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220650 | GEO | 2025/08/06

REPOSITORIES: GEO

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Project description:Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. Due to the lack of an effective medicinal therapy for these tumors, this disease continues to have a tremendous negative impact on women’s health. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyoma. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyoma. An unbiased pathway analysis using a method of gene set enrichment based on the Sigpathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly upregulated pathways in both human and rat tumors. Activation of this pathway was confirmed in both human and rat leiomyomata at the protein level via Western. Inhibition of mTOR in female Eker rats with the rapamycin analog WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly demonstrate the dependence of these tumors on mTOR signaling for growth in the Eker rat. Modulation of this pathway warrants additional investigation as a potential therapy for uterine leiomyoma. Experiment Overall Design: We analyzed 1-3 leiomyoma or normal myometrium biopsies from each 23 woman undergoing hysterectomy for the treatment of uterine fibroids. tment and compared it leiomyoma and normal myometrium from the Eker rat model of uterine fibroids (N=14-15)

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Single-cell atlas of the leiomyoma microenvironment reveals hallmarks of myometrial vascular inflammation

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