Characterization of Sarcomatoid Urothelial Bladder Cancer Features and Treatment Options Using Patient-Derived Organoids - Expert Commentary

Sarcomatoid urothelial bladder cancer (SARC) comprises less than 1% of all bladder cancers and is characterized by early metastasis and poor prognosis. SARC is commonly identified alongside conventional urothelial carcinoma (UC), which has led to the hypothesis that they share a common clonal origin. In line with this, molecular studies have identified shared genomic features. Garioni et al. developed patient-derived organoids (PDOs) of SARC, characterized tumor features, and identified potential treatments.

A sample from a patient’s SARC tumor was used to grow PDOs for over three years. The initial tumor exhibited mixed histology with SARC and conventional UC components. The PDO exhibited a bias towards the SARC variant, indicating that they originated from SARC tumor cells or exhibited selective growth in culture. SARC organoids also exhibited significantly higher invasive capacity than organoids derived from patients with UC (p < 0.0001). This finding was replicated in vivo using a xenograft model. The investigators then performed whole exome sequencing to characterize the molecular features of SARC PDOs. Pathogenic mutations in genes commonly occurring in sarcomatoid tumors, such as TP53, RB1, and KRAS, in addition to genetic alterations in epigenetic and epithelial-to-mesenchymal regulators, were identified. The only shared alteration identified in conventional UC PDOs was in TP53.

Next, the researchers conducted high throughput drug screening with 1,110 FDA-approved drugs and 457 clinical compounds. This led to the identification of 53 compounds that inhibited only conventional UC PDO growth, 34 that inhibited SARC PDO growth, and 70 that inhibited growth in both types of organoids. Various concentrations were subsequently tested to generate dose-dependent response curves for a subset of 21 candidates. Among the most effective candidates for both SARC and UC were compounds targeting microtubules, heat shock proteins, proteasomes, and mTOR pathway activity. For SARC PDOs, the most effective candidates were glucocorticoid receptor (GR) agonists or compounds that targeted p53 and AKT pathways. In line with this, SARC PDOs exhibited high GR expression restricted to stromal cells in UC PDOs. This was confirmed in tumor samples. Furthermore, treating SARC PDOs with dexamethasone (Dex), a GR agonist that is administered to cancer patients as an adjuvant, resulted in a loss of mesenchymal-like features and gain of epithelial-like features, indicating that the SARC phenotype can be modulated with effective treatment.

This important study addresses the lack of experimental models for rare tumors like SARC by establishing a PDO that recapitulates the phenotypic and molecular features of SARC. High-throughput drug screening on PDOs can identify potential therapeutic options with implications for novel clinical trials. These findings also pave the way for personalized medicine, whereby patient treatment options can be selected based on the in vitro response of organoids derived from their tumors.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine


  1. Garioni M, Tschan VJ, Blukacz L, et al. Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer. NPJ Precis Oncol. 2023;7(1):112. Published 2023 Nov 2. doi:10.1038/s41698-023-00466-w

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