Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of a long-term 3D organoid-like model derived from a SARC patient (SarBC-01).
SarBC-01 emulates aggressive morphological, phenotypical, and transcriptional features of SARC and harbors somatic mutations in genes frequently altered in sarcomatoid tumors such as TP53 (p53) and RB1 (pRB). High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and conventional urothelial carcinoma (UroCa) organoids, identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, including agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts and in organoid models, GR and its encoding gene NR3C1 were found to be significantly more expressed in SARC as compared to UroCa, suggesting that high GR expression is a hallmark of SARC tumors. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.
NPJ precision oncology. 2023 Nov 02*** epublish ***
Michele Garioni, Viviane J Tschan, Lauriane Blukacz, Sandro Nuciforo, Romuald Parmentier, Luca Roma, Mairene Coto-Llerena, Heike Pueschel, Salvatore Piscuoglio, Tatjana Vlajnic, Frank Stenner, Hans-Helge Seifert, Cyrill A Rentsch, Lukas Bubendorf, Clémentine Le Magnen
Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland., Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland., Department of Urology, University Hospital Basel, Basel, Switzerland., Division of Medical Oncology, University Hospital Basel, Basel, Switzerland., Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37919480
Read an Expert Commentary by Bishoy Faltas, MD