Deciphering pathogenesis of endometriosis and concomitant infertility using cutting-edge endometrium and implantation models

Endometriosis is a widespread and burdening gynecological disorder. To date, little is known on its pathogenesis, neither on the mechanisms behind its prominently associated infertility. We recently established in vitro organoid models of the ectopic endometrial lesions as well as the endometrium of endometriosis patients, both faithfully reproducing the original tissues. These organoid models now allow to profoundly search for mechanisms underlying endometriosis pathogenesis and associated infertility. Here, we will focus on the HGF-PI3K/AKT and epithelial-mesenchymal transition pathways, both linked to the central inflammatory component of the disease, all together found upregulated in patients’ primary lesions and derived organoids. The same pathways will also be queried for involvement in deficient endometrial functioning in endometriosis, particularly regarding receptivity for, and interaction with, the embryo. Patient endometrial organoids will be applied together with our recently designed unique in vitro implantation model which combines high-fidelity human embryo models (blastoids) with organoid-derived endometrium mimics. Molecular and cellular processes will be scrutinized using cutting-edge single-cell multi-omics, followed by functional validation through pathway interference. Together, our project will provide deep insight into what goes awry in endometriosis and its infertility, with perspectives to discovering novel therapeutic targets.