Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

Imle, Roland; Kommoss, Felix K.F.; Banito, Ana

doi:10.3390/jcm10081578

Cited by 17 publications

(21 citation statements)

References 199 publications

(168 reference statements)

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“…Currently available preclinical models of RMS include conventional cell lines, various genetically engineered animal models (GEMs), as well as patient‐derived xenograft models (PDX or O‐PDX when transplanted orthotopically; Kashi et al , 2015; Imle et al , 2021). Each of these systems possesses specific benefits and drawbacks, resulting in suitabilities for different research questions or stages in drug development (Kim et al , 2020).…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

et al. 2022

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“…Importantly, PDX models are highly predictive of clinical treatment response. 260 This is evident in the response rates to standard chemotherapeutic and targeted therapies in PDX models correlating well with clinical outcome for a number of cancer patients including those with colorectal, pancreatic, non-small cell lung and breast cancer. [261][262][263][264][265] Several studies have reported successful establishment of STS and bone sarcoma PDX models, with an overall engraftment success rate of 32-69% and successful recapitulation of the genetic and phenotypic characteristics of the original tumor.…”

Section: Personalized Precision Medicinementioning

confidence: 94%

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Damerell

Pepper

Prince

2021

Sig Transduct Target Ther

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Sarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

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“…Currently available preclinical models of RMS include conventional cell lines, various genetically engineered animal models (GEMs), as well as patient-derived xenograft models (PDX or O-PDX when transplanted orthotopically) (Imle et al, 2021; Kashi et al, 2015). Each of these systems possesses specific benefits and drawbacks, resulting in suitabilities for different research questions or stages in drug development (Kim et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Meister

Koerkamp

Souza

et al. 2022

Preprint

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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 pediatric RMS tumor organoid (tumoroid) models comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within four to eight 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 six 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.

show abstract

Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

Cited by 17 publications

References 199 publications

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

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