laparoscopic-induction-endometriosis-preclinical-swine-model

Laparoscopic Induction of Endometriosis in a Preclinical Swine Model by Autologous Endometrial Transplantation

Pigs are increasingly used as models of human diseases, largely because their anatomy, physiology, and genetics more closely resemble those of humans. ...

University of Missouri

Korea University Guro Hospital, Korea University College of Medicine

Estrogen receptor α (ESR1) is a pivotal regulator of endometrial homeostasis and reproductive function, yet the coregulators that fine tune its transcriptional activity remain incompletely defined. In this issue of the JCI, Hewitt et al. identified Zinc finger MIZ-type containing 1 (ZMIZ1) as an ESR1 coregulator that is essential for stromal proliferation, decidualization, and overall endometrial integrity. ZMIZ1 deficiency was associated with endometriosis and endometrial cancer, and conditional ablation of Zmiz1 using the PgrCre mouse led to infertility and accelerated fibrosis due to impaired estrogen responsiveness. These findings position ZMIZ1 as a key modulator of estrogen signaling with translational potential as both a biomarker and a therapeutic target in uterine disorders.

ZMIZ1 and estrogen receptor α form an essential partnership in endometrial biology.

Endometriosis affects approximately 10% of reproductive-aged women worldwide and is a leading cause of chronic pelvic pain. Despite its high prevalence and substantial socioeconomic burden, the mechanisms underlying endometriosis-associated pain remain incompletely understood, resulting in delayed diagnosis and limited therapeutic durability. Notably, pain severity frequently shows poor correlation with lesion burden, indicating that endometriosis-associated pain extends beyond the presence of endometriotic lesions alone. Accumulating evidence supports a model in which endometriosis-associated pain arises from the convergence of endocrine dysregulation, immune activation, aberrant neuroangiogenesis, and maladaptive neural plasticity, with estrogen dominance and progesterone resistance serving as central upstream drivers of pain biology. Estrogen-dependent inflammation and progesterone resistance establish a permissive microenvironment that promotes immune dysfunction, neurotrophic signaling, and nociceptor sensitization. These peripheral processes drive sustained afferent input to the central nervous system, leading to peripheral, central, and cross-organ sensitization that can perpetuate pain independently of lesion activity. In this review, we synthesize current evidence across the clinical spectrum of pain, mechanistic pathways, and therapeutic approaches in endometriosis. We integrate insights from inflammatory and immune pathways, neuroimmune crosstalk, hormonal regulation, and sensitization processes, emphasizing progesterone resistance and estrogen-mediated signaling as central modulators. Advances from preclinical models and emerging multi-omics technologies are highlighted to define pain signatures that transcend lesion-based classification. Finally, we discuss emerging therapeutic strategies targeting neuroimmune and endocrine pathways and propose a precision medicine framework that incorporates mechanistic biomarkers, translational models, and pain-specific clinical endpoints to improve stratification, reduce ineffective interventions, and achieve individualized pain relief for women with endometriosis.

Endometriosis-associated Pain: Mechanism, Neuroimmune Signature, and Translational Precision Strategies.

Endometrioid endometrial cancer (EEC) is the most prevalent gynecological malignancy. While early-stage EEC typically carries a favorable prognosis, late-stage EEC shows significantly poorer outcomes, with a five-year survival rate of only 17-19%. Co-occurring PTEN and CTNNB1 variants are frequent in EEC and linked to poor prognosis. To investigate their functional impact, we generated uterine-specific Pten knockout mice and dominantly stabilized Ctnnb1 mutant mice (Pgrcre/+Ptenf/fCtnnb1f(ex3)/+; Ptend/dCtnnb1f(ex3)/+). These double-mutant mice exhibited significantly reduced survival compared to single Pten knockout (Pgrcre/+Ptenf/f; Ptend/d) mice. Histopathology revealed aggressive, metastatic endometrioid cancer in Ptend/dCtnnb1f(ex3)/+ mice; these mice developed myometrial invasion by four weeks of age - unlike Ptend/d mice. Transcriptomic analysis identified activation of multiple oncogenic pathways, including WNT/CTNNB1, PI3K/AKT, basal cell carcinoma, sonic hedgehog signaling and epithelial-mesenchymal transition (EMT). Immunohistochemistry confirmed hallmark features of EMT in the uterus of double-mutant mice, including strong downregulation of E-cadherin (CDH1) and upregulation of the EMT regulator SNAIL (Snai1). These findings demonstrate that synergistic mutations of PTEN and CTNNB1 promote early invasion, EMT activation, and metastatic progression, offering mechanistic insight into the aggressive behavior and poor clinical outcomes associated with this subtype of EEC.

Article	Year
ZMIZ1 and estrogen receptor α form an essential partnership in endometrial biology. The Journal of clinical investigation\| PubMed ID: 41321319	2025
Endometriosis-associated Pain: Mechanism, Neuroimmune Signature, and Translational Precision Strategies. Endocrine reviews\| PubMed ID: 42267663	2026
Co-mutations of CTNNB1 and PTEN drive aggressive tumor progression in endometrial cancer. Disease models & mechanisms\| PubMed ID: 42312452	2026

Kyeong A So

Biography

JoVE Journal Publications

Other Publications