20/#1057 Integrated profiling of a prospective endometrial cancer organoid biobank reveals high heterogeneity. (4th December 2022) - Berg, Hege
Abstract : Objectives: Patient-derived cancer organoids have quickly developed as valuable tools for drug testing as they better represent the genetic background of the patient cohort. We recently published a protocol for establishing EC organoids from all types and grades of EC (Berg et al, Nat Comms Med 2021). We here present data from a prospectively collected biobank of organoids including all EC molecular subclasses. Models have been extensively profiled and evaluated for drug response, supporting high heterogeneity in EC. Methods: Organoids were prospectively derived from resected EC tissue from consenting patients and cultured long-term in a chemically defined medium. Orthotopic xenograft mouse models, representing all subtypes of EC, were established by intra-uterine injection of organoids. All organoids were characterized by IHC, WES and RNA sequencing, and by single cell phenotyping. Organoids were treated with carboplatin, paclitaxel, and small molecule inhibitors against PARP, CHEK1/2, PIK3CA/mTOR, and CDK4/6. Results: The organoids reflect the main molecular EC subtypes, including POLE, MSI, copy-number low and copy-number high models. We identified matched molecular alterations in patient tissue and corresponding organoids, even after long-term culturing and expansion in vivo. Model-specific chemotherapy responses were observed and reproduced in mouse models for selected organoids. Carboplatin-resistant organoids had more alterations in platinum-related genes, including BAX, DAB2IP, ATM and CASP2. However, type of genetic alteration differed between the resistant organoids. Treatment with small-molecule inhibitors identified heterogenous drug responses. Conclusions: This state-of-the-art preclinical platform provides clinically relevant tools for use in preclinical drug trials.