IBCN 2023: Patient-Derived Organoids Identify Tailored Therapeutic Options and Determinants of Plasticity in Sarcomatoid Urothelial Bladder Cancer

(UroToday.com) Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer. Here, we established the first long-term 3D organoid-like model derived from a SARC patient (SarBC-01) and used it to identify potential therapeutic strategies and factors driving bladder cancer progression.

Samples were collected from one SARC patient (SarBC-01) undergoing transurethral resection of the bladder (TURB) and three conventional urothelial carcinoma (UroCa) patients undergoing cystectomy or TURB, and were subsequently processed to generate organoids. Organoids were characterized using H&E staining, immunohistochemistry (IHC), immunofluorescence, and whole-exome sequencing and subjected to in vitro invasion and in vivo tumorigenicity assays. A library of 1567 drugs was tested at single concentration and 26 drugs were validated in dose response analysis. Glucocorticoid receptor expression was assessed using bulk RNA sequencing public dataset and IHC in an in-house cohort. Single-cell RNA sequencing was performed following the protocol of Chromium GEM v3.1 (10 xGenomics).

SarBC-01 emulated morphological and phenotypical features of SARC and harbored somatic mutations in genes frequently altered in sarcomatoid tumors such as TP53 and RB1. SarBC-01 exhibited significant higher invasive capacity in vitro and faster tumorigenicity in vivo than UroCa-derived organoids, consistent with a more aggressive phenotype. High-throughput drug screening identified drug candidates active against SARC cells exclusively, UroCa cells exclusively, or both. Agents targeting the Glucocorticoid Receptor (GR) pathway were specifically effective in SARC cells. In two independent cohorts, GR expression was significantly higher and more frequent in SARC versus UroCa samples, suggesting that high GR expression represents a hallmark of SARC tumors. Further, glucocorticoid treatment abrogated the invasive ability of SARC cells and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition.

In summary, this study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.

Presented by: Michele Garioni, Institute of Medical Genetics and Pathology, Department of Urology, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.

Written by: Stephen B. Williams, MD, MBA, MS @SWilliams_MD on Twitter during the International Bladder Cancer Network (IBCN) Annual Meeting, September 29-30, 2023, Montreal, Canada