Editors' ChoiceCancer

Modeling endometrial disease using organoids

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Science Translational Medicine  28 Aug 2019:
Vol. 11, Issue 507, eaaz0304
DOI: 10.1126/scitranslmed.aaz0304

Abstract

Organoids generated from patient-derived endometrial tissue model the pathophysiology of endometrial disease and can be used for drug screening.

Endometrial disease is a major gynecological concern and includes a wide range of pathophysiological processes: hyperplasia, infertility, Lynch syndrome, and cancer. Although the clinical relevance and importance of studying these disorders is apparent, there is a lack of preclinical models of endometrial disease available for evaluating therapies.

To address this challenge, Boretto and colleagues established three-dimensional patient-derived endometrial organoid models. Organoids from all clinical stages of endometrial pathology—healthy, endometriosis, precancerous, and malignant—preserved the main characteristics of the primary tissue, including disease heterogeneity and patient genetic background. These could be cultured and expanded in vitro, thus reducing the dependence on primary biopsy tissue availability and facilitating pathogenetic studies. Endometrial cancer organoids (EC-O) presented a low establishment efficiency that required special media optimization: decreased p38 inhibition and addition of hepatocyte and insulin-like growth factors. The EC-O retained primary tumor–associated markers and mutations even after extensive in vitro expansion, enabling the identification of multiple cancer driver gene candidates for this disease. When comparing organoids derived from cancer lesions with those derived from healthy tissues, the authors discovered several signaling alterations in WNT and phosphoinositide 3-kinase (PI3K)–AKT pathways, among others, as well as cancer-associated mutations. EC-O reproduced the hormone receptor phenotype of the original tumors, expression of functional ion channels, patient-specific drug responses and, most importantly, could be transplanted orthotopically into mice for in vivo studies. Therefore, these models could be used as a biobank to study endometrial disease pathogenesis and to evaluate new treatments beyond hormonal suppression and chemotherapy.

The authors elegantly described the development and characterization of culture-expandable organoids that recapitulate endometrial disease pathologies, reliably reproducing gynecological lesion attributes. These organoids can be used as research models and as a powerful drug screening platform to find new therapies against these complex disorders, with a special focus on personalized medicine and cancer treatment.

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