Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

• Published in: EMBO molecular medicine Vol. 14; no. 10; pp. e16001 - n/a
• Main Authors: Meister, Michael T, Groot Koerkamp, Marian J A, de Souza, Terezinha, Breunis, Willemijn B, Frazer‐Mendelewska, Ewa, Brok, Mariël, DeMartino, Jeff, Manders, Freek, Calandrini, Camilla, Kerstens, Hinri H D, Janse, Alex, Dolman, M Emmy M, Eising, Selma, Langenberg, Karin P S, van Tuil, Marc, Knops, Rutger R G, van Scheltinga, Sheila Terwisscha, Hiemcke‐Jiwa, Laura S, Flucke, Uta, Merks, Johannes H M, van Noesel, Max M, Tops, Bastiaan B J, Hehir‐Kwa, Jayne Y, Kemmeren, Patrick, Molenaar, Jan J, van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno, Holstege, Frank C P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-10-2022; EMBO Press; Springer Nature
• Subjects: Acquisitions & mergers; Bone marrow; Cancer therapies; Child; Children; CRISPR; CRISPR/Cas9; Drug screening; EMBO03; EMBO22; Genes; Histology; Humans; Lymphatic system; mesenchymal; Mesenchyme; Metastasis; Organoids; Organoids - pathology; p53 Protein; Patients; Pediatrics; Propagation; Rhabdomyosarcoma; Rhabdomyosarcoma - diagnosis; Rhabdomyosarcoma - pathology; Sarcoma; tumoroid; Tumors; tumoroid; CRISPR/Cas9; rhabdomyosarcoma; mesenchymal; drug screening
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202216001

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.
Synopsis
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.
This is the first collection of purely mesenchymal tumoroid models and only the second tumoroid collection of pediatric cancers.
RMS tumoroid models faithfully recapitulate molecular alterations of the parent tumor with retained transcriptional and clonal heterogeneity.
They are rapidly established and expanded with the ability to perform drug screening as fast as 27 days after sample acquisition (median 81 days).
Lastly, they are amenable to CRISPR/Cas9 editing to recapitulate mutations conferring poor prognosis in RMS (e.g., in
TP53
).
Graphical Abstract
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.