Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Michael T Meister; Marian J A Groot Koerkamp; Terezinha de Souza; Willemijn B Breunis; Ewa Frazer-Mendelewska; Mariël Brok; Jeff DeMartino; Freek Manders; Camilla Calandrini; Hinri H D 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

doi:10.15252/emmm.202216001

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Michael T Meister, Marian J A Groot Koerkamp, Terezinha de Souza, Willemijn B Breunis, Ewa Frazer-Mendelewska, Mariël Brok, Jeff DeMartino, Freek Manders, Camilla Calandrini, Hinri H D 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 MerksMax 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

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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.

Original language	English
Article number	e16001
Journal	Embo Molecular Medicine
Volume	14
Issue number	10
Early online date	2 Aug 2022
DOIs	https://doi.org/10.15252/emmm.202216001
Publication status	Published - 10 Oct 2022

Keywords

CRISPR/Cas9
drug screening
mesenchymal
rhabdomyosarcoma
tumoroid

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EMBO Mol Med - 2022 - Meister - Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypesFinal published version, 6.64 MBLicence: CC BY

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Meister, M. T., Groot Koerkamp, M. J. A., de Souza, T., Breunis, W. B., Frazer-Mendelewska, E., Brok, M., DeMartino, J., Manders, F., Calandrini, C., Kerstens, H. H. D., Janse, A., Dolman, M. E. M., Eising, S., Langenberg, K. P. S., van Tuil, M., Knops, R. R. G., van Scheltinga, S. T., Hiemcke-Jiwa, L. S., Flucke, U., ... Holstege, F. C. P. (2022). Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes. Embo Molecular Medicine, 14(10), Article e16001. https://doi.org/10.15252/emmm.202216001

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title = "Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes",

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.",

keywords = "CRISPR/Cas9, drug screening, mesenchymal, rhabdomyosarcoma, tumoroid",

author = "Meister, {Michael T} and {Groot Koerkamp}, {Marian J A} and {de Souza}, Terezinha and Breunis, {Willemijn B} and Ewa Frazer-Mendelewska and Mari{\"e}l Brok and Jeff DeMartino and Freek Manders and Camilla Calandrini and Kerstens, {Hinri H D} and Alex Janse and Dolman, {M Emmy M} and Selma Eising and Langenberg, {Karin P S} and {van Tuil}, Marc and Knops, {Rutger R G} and {van Scheltinga}, {Sheila Terwisscha} and Hiemcke-Jiwa, {Laura S} and Uta Flucke and Merks, {Johannes H M} and {van Noesel}, {Max M} and Tops, {Bastiaan B J} and Hehir-Kwa, {Jayne Y} and Patrick Kemmeren and Molenaar, {Jan J} and {van de Wetering}, Marc and {van Boxtel}, Ruben and Jarno Drost and Holstege, {Frank C P}",

note = "Funding Information: We thank the patients and their parents for contributing by consenting to this study; the nurses, doctors, and other health care professionals in our institute with whom we work closely; our center's high‐throughput screening facility, in particular Bianca Koopmans, Kimberley Ober, and Sander van Hooff; Philip Lijnzaad, Thanasis Margaritis, and Tito Candelli from our center's single‐cell genomics facility, as well as past and present members of the Holstege group. MTM received financial support from the Deutsche Forschungsgemeinschaft (#408083583). CC was supported by Children Cancer‐free Foundation (Stichting Kinderen Kankervrij; #292). JDr received support from the European Research Council (ERC) starting grant #850571 and the Dutch Cancer Society (KWF)/Alpe d'HuZes Bas Mulder award (#10218). We are grateful for the financial support provided by the Foundation Children Cancer‐free (Stichting Kinderen Kankervrij core funding). Publisher Copyright: {\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",

year = "2022",

month = oct,

day = "10",

doi = "10.15252/emmm.202216001",

language = "English",

volume = "14",

journal = "Embo Molecular Medicine",

issn = "1757-4676",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "10",

}

Meister, MT, Groot Koerkamp, MJA, de Souza, T, Breunis, WB, Frazer-Mendelewska, E, Brok, M, DeMartino, J, Manders, F, Calandrini, C, Kerstens, HHD, Janse, A, Dolman, MEM, Eising, S, Langenberg, KPS, van Tuil, M, Knops, RRG, van Scheltinga, ST, Hiemcke-Jiwa, LS, Flucke, U, Merks, JHM, van Noesel, MM, Tops, BBJ, Hehir-Kwa, JY, Kemmeren, P, Molenaar, JJ, van de Wetering, M, van Boxtel, R, Drost, J & Holstege, FCP 2022, 'Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes', Embo Molecular Medicine, vol. 14, no. 10, e16001. https://doi.org/10.15252/emmm.202216001

TY - JOUR

T1 - Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

AU - Meister, Michael T

AU - Groot Koerkamp, Marian J A

AU - de Souza, Terezinha

AU - Breunis, Willemijn B

AU - Frazer-Mendelewska, Ewa

AU - Brok, Mariël

AU - DeMartino, Jeff

AU - Manders, Freek

AU - Calandrini, Camilla

AU - Kerstens, Hinri H D

AU - Janse, Alex

AU - Dolman, M Emmy M

AU - Eising, Selma

AU - Langenberg, Karin P S

AU - van Tuil, Marc

AU - Knops, Rutger R G

AU - van Scheltinga, Sheila Terwisscha

AU - Hiemcke-Jiwa, Laura S

AU - Flucke, Uta

AU - Merks, Johannes H M

AU - van Noesel, Max M

AU - Tops, Bastiaan B J

AU - Hehir-Kwa, Jayne Y

AU - Kemmeren, Patrick

AU - Molenaar, Jan J

AU - van de Wetering, Marc

AU - van Boxtel, Ruben

AU - Drost, Jarno

AU - Holstege, Frank C P

N1 - Funding Information: We thank the patients and their parents for contributing by consenting to this study; the nurses, doctors, and other health care professionals in our institute with whom we work closely; our center's high‐throughput screening facility, in particular Bianca Koopmans, Kimberley Ober, and Sander van Hooff; Philip Lijnzaad, Thanasis Margaritis, and Tito Candelli from our center's single‐cell genomics facility, as well as past and present members of the Holstege group. MTM received financial support from the Deutsche Forschungsgemeinschaft (#408083583). CC was supported by Children Cancer‐free Foundation (Stichting Kinderen Kankervrij; #292). JDr received support from the European Research Council (ERC) starting grant #850571 and the Dutch Cancer Society (KWF)/Alpe d'HuZes Bas Mulder award (#10218). We are grateful for the financial support provided by the Foundation Children Cancer‐free (Stichting Kinderen Kankervrij core funding). Publisher Copyright: © 2022 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2022/10/10

Y1 - 2022/10/10

N2 - 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.

AB - 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.

KW - CRISPR/Cas9

KW - drug screening

KW - mesenchymal

KW - rhabdomyosarcoma

KW - tumoroid

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U2 - 10.15252/emmm.202216001

DO - 10.15252/emmm.202216001

M3 - Article

C2 - 35916583

SN - 1757-4676

VL - 14

JO - Embo Molecular Medicine

JF - Embo Molecular Medicine

IS - 10

M1 - e16001

ER -

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

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Keywords

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