Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes
Michael T. Meister, Marian J.A. Groot Koerkamp, Terezinha Souza, Willemijn B. Breunis, Ewa Frazer‐Mendelewska, Mariël Brok, Jeff DeMartino, Freek Manders, Camilla Calandrini, Hinri Kerstens, Alex Janse, M. Emmy M. Dolman, Selma Eising, Karin P.S. Langenberg, Marc van Tuil, Rutger R. G. Knops, Sheila Terwisscha van Scheltinga, Laura S. Hiemcke‐Jiwa, Uta Flucke, Johannes H. M. Merks, Max M. van Noesel, Bastiaan B.J. Tops, Jayne Y. Hehir‐Kwa, Patrick Kemmeren, Jan J. Molenaar, Marc van de Wetering, Ruben van Boxtel, Jarno Drost, Frank C. P. Holstege
Abstract
Rhabdomyosarcomas (RMS) are mesenchyme‐derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high‐risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within 4–8 weeks, indicating the feasibility of personalized drug screening. Molecular, genetic, and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to 6 months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions. The first collection of comprehensively characterized tumor organoid (tumoroid) models of pediatric rhabdomyosarcomas (RMS) as novel preclinical models for this highly aggressive pediatric cancer entity. The first collection of comprehensively characterized tumor organoid (tumoroid) models of pediatric rhabdomyosarcomas (RMS) as novel preclinical models for this highly aggressive pediatric cancer entity.