Distinct subtypes of endometriosis identified based on stromal-immune microenvironment and gene expression: implications for hormone therapy

Abstract

BackgroundEndometriosis (EMs) is a chronic inflammatory condition that is highly heterogeneous. Current clinical staging fails to accurately predict drug responses and prognosis. In this study, we aimed to reveal the heterogeneity of ectopic lesions and investigate the possible underlying mechanisms using transcriptomic data and clinical information.MethodsThe EMs microarray dataset GSE141549 was obtained from the Gene Expression Omnibus database. Unsupervised hierarchical clustering was performed to identify EMs subtypes, which was followed by the functional enrichment analysis and estimation of immune infiltrates. Subtype-associated gene signatures were identified and further validated in other independent datasets, including GSE25628, E-MTAB-694, and GSE23339. Additionally, tissue microarrays (TMAs) were generated from premenopausal patients with EMs to investigate the potential clinical implications of the two identified subtypes.ResultsThe unsupervised clustering analysis revealed that ectopic EMs lesions can be classified into two distinct subtypes: stroma-enriched (S1) and immune-enriched (S2). The functional analysis revealed that S1 correlated with fibroblast activation and extracellular matrix remodeling in the ectopic milieu, whereas S2 was characterized by the upregulation of immune pathways and a higher positive correlation with the immunotherapy response. Moreover, we identified a subtype signature composed of FHL1 and SORBS1, and constructed a subtype diagnostic model. Based on the cohort data from the TMAs, we found that S2 was strongly associated with the failure of/intolerance to hormone therapy.ConclusionsThis study identified two distinct subtypes that are varyingly associated with hormone resistance, stroma-immunity, and molecular features, thereby highlighting the importance of this stromal-immune heterogeneity in identifying EMs subtypes and providing novel insights into future personalized hormone-free therapy in EMs.

Extracellular succinate derived from ectopic milieu drives adhesion and implantation growth of ectopic endometrial stromal cells via the SUCNR1 signal in endometriosis

“…Tissue microarrays (TMAs) [ 16 ] were previously constructed with endometriosis lesions tissues. Immunohistochemistry (IHC) for succinate dehydrogenase complex iron sulfur subunit (SDHB) was performed according to the manufacturer’s instructions.…”

The IL-33-ST2 axis plays a vital role in endometriosis via promoting epithelial–mesenchymal transition by phosphorylating β-catenin

“…TMAs were established in our previous study [ 28 ]. All ectopic tissues used for the TMAs construction were diagnosed as EMs by an experienced gynecological pathologist.…”

Bioengineering approaches for the endometrial research and application

“…However, the regenerative abilities of the endometrium may be lost because of impaired hormonal response caused by serious pathological alterations or physiological aging. Steroid-dependent events in the endometrium are altered in endometriosis and adenomyosis, possibly owing to chronic inflammation [ 20 , 21 ]. The hormonal response and endometrial regeneration also disappear in cases of Asherman's syndrome and a thin endometrium due to disruptions of endometrial cell composition [ 22 ].…”

“…The discovery of lesion heterogeneity further plays a crucial role in drug screening and personalized treatment. Besides, more recently, researchers noticed that the pathological characteristics of endometriosis are linked to the diseased condition of endometrial cells and to the microenvironment where the lesion occurs [ 20 ]. Such an understanding promotes the addition of microfluidics to endometriosis organoid modeling systems, providing well-controlled platforms by regulating nutrient supply and waste removal.…”