Kras mutation in eutopic endometrium and development of endometriosis : a novel mouse model

Endometriosis is a gynaecological condition that affects 10-15% of people with a uterus and is defined when endometrial-like tissue forms lesions in ectopic environments, most commonly within the pelvic cavity [1, 2]. The reflux of eutopic endometrium into the pelvic cavity, via retrograde menstruation, is the most common explanation for endometriosis development; however, more factors (such as gene expression alterations and immune dysregulation) are likely to contribute to the development of endometriotic lesions [3, 4]. It has recently been discovered that patients with deep infiltrating endometriosis, an invasive subtype of endometriosis, tend to have a mutation in KRAS codon 12 confined to the epithelium of the endometriosis lesions and within the eutopic endometrium [5]. To achieve a deeper understanding of the roles of the KRAS mutation in the development of endometriosis, this thesis has two aims: 1) compare the morphology and expression profiles between Kras-mutant and Kras-wildtype eutopic endometrium and 2) develop a novel mouse model for endometriosis with epithelium-restricted Kras mutation. In Aim 1, I found significant downregulation of genes related to the extracellular matrix and upregulation of genes involved in inflammation in Kras-mutant compared to Kras-wildtype uterine tissue. Furthermore, differential regulation of genes involved in epithelial-mesenchymal transition, decidualization, and ferroptosis were also identified. The differential expression of various genes between Kras-mutant and wildtype uterine tissue may partially explain the development of endometriosis and associated symptoms. Aim 2 investigates this potential role of Kras mutations in the development of endometriosis; however, lesion establishment was unsuccessful. Nonetheless, this model provided a good framework to inform the development of future endometriosis mouse models. The characterization of differentially regulated genes between mutated and wildtype endometrial tissue could have large implications in future preclinical studies that focus on the role of somatic mutations in the proliferation and growth of the invasive tissue, with the end goal of developing novel personalized treatments suitable for patients affected by endometriosis.