Endometriosis, marked by uterine-like tissue called the endometrium growing outside the organ, affects nearly 10 percent of reproductive-age women. Although it causes severe pelvic pain and sometimes infertility, there is no cure for the disease. Treatment focuses on symptom management. Despite its prevalence and severity, the mechanism of the disease remains poorly understood.1
Some researchers hypothesize that retrograde menstruation, the backflow of menstrual blood into the pelvic cavity, deposits endometrial cells there, which eventually grow into painful lesions.1 “Retrograde menstruation happens in almost 80 to 90 percent of the women, but only 10 to 15 percent of these women have endometriosis,” said Xiaoyan Li, a gynecologist at the Chinese Academy of Medical Sciences (CAMS). Li, together with Xiaoyue Wang, a genomics researcher at CAMS, sought to understand why not all retrograde menstruation results in endometriosis.
In a recent study, Wang and her team identified a signaling pathway that may promote the attachment and growth of endometrial cells outside the uterus.2 Their findings, published in Cell Genomics, reveal insights about interactions between cells in the diseased tissue that can guide the development of treatments.
“This [study] represents an important advance in endometriosis analysis. Endometriosis has been really understudied,” said Kate Lawrenson, a women’s health expert at the University of Texas Health Science Center at San Antonio. This research, along with some other recent studies, sheds light on what exactly endometriosis cells look like, she added.
Wang and her team started by collecting cells from endometriotic ovarian cysts, called endometriomas. Single-cell sequencing revealed that some of the cells within these lesions were endometrial stromal cells, which regulate the shedding and regrowth of the healthy endometrium. The team compared this data with another group’s earlier findings and observed similar cell composition in both diseased and healthy tissues.3
Since hormones regulate the shedding of uterine endometrium during menstruation and ectopic lesions are known to bleed cyclically, the researchers investigated whether endometrioma cells retain hormone responsiveness.4 To do so, the team analyzed the transcriptomes of cells in endometriomas and observed that the cells maintained menstrual cycle gene expression patterns. On comparing the transcriptomes of healthy tissue and endometriotic lesions, the researchers observed an aberrant overexpression of some genes associated with wound healing and inflammation in the latter.
In addition to exhibiting endometrial traits, some lesion cells also showed ovarian-like characteristics, which were absent in the uterine endometrium. Spatial transcriptome sequencing of three endometriomas revealed an organized structure within the lesions: The region containing ectopic endometrial stromal cells was enriched in immune cells and these were surrounded by two types of ovarian cells. Compared to cells in the healthy ovary, the ovarian cell subtypes in the lesions showed elevated expression of genes associated with inflammation and fibrosis.
Wang and her team next explored the signaling pathways that underlie the interactions between these different cells in the lesions and the environment. They used a bioinformatic tool that analyzes intercellular communication networks from single-cell sequencing data.5 This helped them identify biochemical pathways present in the lesions, where ectopic endometrial stromal cells and ovarian cells dominated the outgoing signals while immune cells primarily received the signals.
Among the pathways originating from ectopic endometrial stromal cells, the non-canonical WNT pathway, which usually regulates the expression of cell migration-related genes, showed the highest interaction strength with ovarian cells.6 Wang and team further analyzed the communication probabilities to home in on the specific ligand-receptor pair involved in this signaling. This helped them identify that ectopic endometrial stromal cells secrete the ligand WNT5A, which acts on the ovarian cells through the receptor Frizzled-1.
“We think [WNT5A] might be responsible for connecting the ectopic endometrioma with its environment to sustain its growth,” said Wang. However, the signaling pathway also plays an important role in healthy cells, she added. “[So], we need to be cautious for using it as therapy.”
“[The study] gives some molecular granularity that we haven’t known before,” said Lawrenson. Although this offers potential therapeutic targets, she noted that the researchers have looked at cells from only a few participants. “We're going to need bigger studies representing diverse groups of patients to make the most definitive conclusions and observations.”
Song Liu, a computational biologist and study coauthor said that future work will involve exploring whether the signaling pathway is a viable therapeutic target using experimental animal models. The team also aims to investigate whether similar pathways operate in endometriosis lesions other than those found on the ovaries.
- Taylor HS, et al. Endometriosis is a chronic systemic disease: Clinical challenges and novel innovations. Lancet. 2021;397(10276):839-852.
- Liu S, et al. Single-cell and spatial transcriptomic profiling revealed niche interactions sustaining growth of endometriotic lesions. Cell Genom. 2025;5(1):100737.
- Fonseca MAS, et al. Single-cell transcriptomic analysis of endometriosis. Nat Genet. 2023;55(2):255-267.
- Brosens IA. Endometriosis—A disease because it is characterized by bleeding. Am J Obstet Gynecol. 1997;176(2):263-267.
- Jin S, et al. Inference and analysis of cell-cell communication using CellChat. Nature Commun. 2021;12(1):1088
- Liu J, et al. Wnt/β-catenin signalling: Function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7(1):3.
