Barbi, Mali, Gupta, Shalini, Subhash, Santhilal, Gowthaman, Divya, Katcher, Arielle, Gorman, Megan, Yueh, Brian, Akyildiz, Erdogan, Mahesh, Uma, Gee, Devin, Chambwe, Nyasha, Chung, Charlie, Frimer, Marina, Goldberg, Gary L, Beyaz, Semir (April 2026) A comprehensive endometrial cancer organoid biobank reveals subtype-specific transcriptional programs and therapeutic targets. In: American Association for Cancer Research Annual Meeting 2026, 2026 Apr 17-22, San Diego, CA.
Abstract
Endometrial cancer (EC) is a clinically and biologically heterogeneous disease with unequal outcomes, particularly among high-grade tumors that disproportionately affect racially diverse populations. Existing preclinical models incompletely capture this heterogeneity. We established a large, racially diverse EC patient-derived organoid (PDO) biobank with matched normal to define subtype-specific molecular programs and actionable vulnerabilities. Tumors and matched normal endometrium were prospectively collected (n=380). Morphologic fidelity was assessed by histology and immunophenotyping. Multi-omic profiling evaluated driver retention and defined subtype-specific transcriptional states. High-throughput drug screening identified candidate vulnerabilities. A total of 319 samples were included, with a ∼93% PDO establishment rate, and matched tumor-normal PDOs generated across major EC histologies. PDOs recapitulated the key architectural and protein-expression features of their parental tumors, including TP53-abnormal serous phenotypes and mixed epithelial-mesenchymal organization in carcinosarcoma (CS). PDOs also preserved the key genomic characteristics, including TP53, PTEN, and PIK3CA alterations. Transcriptomic profiling revealed distinct subtype programs. Endometrioid PDOs showed Wnt-associated epithelial renewal with reduced apoptosis, p53, mTORC1, and inflammatory signaling. Serous PDOs displayed TP53-abnormal, MYC-and cell-cycle-enriched programs with uniformly suppressed interferon signaling. CS exhibited hybrid epithelial-mesenchymal features with activation of Hedgehog and myogenic pathways and broad suppression of NF-kB and interferon signaling. Stratification by p53 stability and MSI status defined opposing hyperproliferative versus immune-active axes. High-throughput drug screening identified class I HDAC inhibitor (romidepsin, RD) as a consistent activity signal. RD-perturbation RNA-seq in CS showed extensive remodeling at 10 nM, with downregulation of core G2-M/E2F mitotic regulators and suppression of CS-associated secreted factors, accompanied by restoration of antigen-presentation and interferon-responsive genes. Pathway analysis demonstrated coordinated suppression of mitotic modules and reactivation of cytokine and immune signaling. RD inhibited the TPX2-CDK1-KIF11 mitotic module, indicating a druggable spindle-dependency circuit in CS. This large, racially diverse EC PDO biobank provides a robust preclinical platform that captures EC heterogeneity and enables controlled, subtype-resolved analyses. Integrated multi-omics and functional perturbation identify a spindle-dependency axis in CS, supporting subtype-specific and ancestry-aware therapy development.
| Item Type: | Conference or Workshop Item (Poster) |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > endometrial cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Beyaz lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 3 April 2026 |
| Date Deposited: | 22 Apr 2026 12:41 |
| Last Modified: | 22 Apr 2026 12:41 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42171 |
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