Preclinical in Vivo Modeling of Pediatric Sarcoma—Promises and Limitations
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Journal of Clinical Medicine Review Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations Roland Imle 1,2,3,4 , Felix K. F. Kommoss 1,2,5 and Ana Banito 1,2,* 1 Hopp Children’s Cancer Center, Heidelberg (KiTZ), 69120 Heidelberg, Germany; [email protected] (R.I.); [email protected] (F.K.F.K.) 2 Pediatric Soft Tissue Sarcoma Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 3 Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany 4 Department of General, Visceral and Transplantation Surgery, Division of Pediatric Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany 5 Institute of Pathology, University of Heidelberg, 69120 Heidelberg, Germany * Correspondence: [email protected] Abstract: Pediatric sarcomas are an extremely heterogeneous group of genetically distinct diseases. Despite the increasing knowledge on their molecular makeup in recent years, true therapeutic advancements are largely lacking and prognosis often remains dim, particularly for relapsed and metastasized patients. Since this is largely due to the lack of suitable model systems as a prerequisite to develop and assess novel therapeutics, we here review the available approaches to model sar- coma in vivo. We focused on genetically engineered and patient-derived mouse models, compared strengths and weaknesses, and finally explored possibilities and limitations to utilize these models to advance both biological understanding as well as clinical diagnosis and therapy. Citation: Imle, R.; Kommoss, F.K.F.; Keywords: pediatric sarcoma; animal models; GEMMs; PDXs; preclinical testing Banito, A. Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations. J. Clin. Med. 2021, 10, 1578. https:// 1. Introduction doi.org/10.3390/jcm10081578 Sarcomas are mesenchymal malignancies accounting for about 15% of cancers in children and adolescents, making them the third most common group of childhood cancers, Academic Editor: following blood malignancies and brain tumors [1]. While the last decades have seen vast Raushan Kurmasheva improvements in pediatric cancer care with overall improved prognosis, this does not hold true for sarcomas, which are often prone to metastasis and relapse, typically accompanied Received: 27 February 2021 by dismal prognosis [2]. Research efforts to improve this situation are complicated by Accepted: 6 April 2021 Published: 8 April 2021 the extremely diverse intrinsic nature of pediatric sarcoma with more than 60 genetically distinct entities [3]. While some pediatric sarcoma types may show widespread genomic Publisher’s Note: MDPI stays neutral instability (e.g., osteosarcoma (OS)), many are genetically rather simple, characterized with regard to jurisdictional claims in by pathognomonic fusion oncogenes (e.g., SSX-SS18 in Synovial Sarcoma (SySa)) [4–6]. published maps and institutional affil- Ongoing molecular profiling efforts will likely lead to further sub-classification as we learn iations. more about specific genetic and epigenetic alterations and underlying biology [7]. Figure1 provides a snapshot of the most common pediatric sarcoma types according to the recently (2020) updated World Health Organization (WHO) classification of soft tissue and bone tumors (Figure1a) [ 8,9], as well as an unbiased molecular clustering of the most common tumor entities based on DNA methylation data (Figure1b) [ 10]. The development of novel Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. therapeutic agents heavily relies on preclinical testing in disease specific models. Given This article is an open access article the rarity of each individual pediatric sarcoma subtype, appropriate model systems are distributed under the terms and naturally scarce, and the selection of suitable models is challenging. This represents a conditions of the Creative Commons major problem for pediatric cancer research and has significantly contributed to the lack of Attribution (CC BY) license (https:// meaningful therapeutic improvements in pediatric sarcomas [11]. Therefore, in this review, creativecommons.org/licenses/by/ we aim to outline the pros and cons of major in vivo modeling approaches applicable for 4.0/). pediatric sarcoma. We review existing models applied for specific sarcoma entities and J. Clin. Med. 2021, 10, 1578. https://doi.org/10.3390/jcm10081578 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 27 J. Clin. Med. 2021, 10, 1578 2 of 27 applicable for pediatric sarcoma. We review existing models applied for specific sarcoma entitiesdiscuss relevantand discuss points relevant to consider points for to meaningful consider for future meaningful model utilization. future model Due utilization. to the vast Duearray to of the known vast malignancies,array of known the scopemalignancies, of this review the scope is limited of this to 18review clinically is limited particularly to 18 clinicallyrelevant sarcoma particularly entities. relevant sarcoma entities. Figure 1.1. TheThe diversediverse landscapelandscape of of pediatric pediatric sarcoma. sarcoma. (A ()A Extraction) Extraction from from the the current current WHO WH classificationO classification of soft-tissue of soft-tissue and and bone tumors (5th edition, 2020) with focus on pediatric sarcoma [8]. (B,C) Molecular classification by whole genome bone tumors (5th edition, 2020) with focus on pediatric sarcoma [8]. (B,C) Molecular classification by whole genome DNA DNA methylation data, here depicted for 18 sarcoma entities relevant for childhood and adolescence. Data shown as methylation data, here depicted for 18 sarcoma entities relevant for childhood and adolescence. Data shown as hierarchical hierarchical clustering analysis, (B) and t-distributed stochastic neighbor embedding (t-SNE), (C) data adapted from B C clusteringKölsche et analysis,al., 2021 [10]. ( ) and t-distributed stochastic neighbor embedding (t-SNE), ( ) data adapted from Kölsche et al., 2021 [10]. 2. In Vivo Modeling Approaches Applicable for Pediatric Sarcoma 2. In Vivo Modeling Approaches Applicable for Pediatric Sarcoma Analogous to other solid tumors, four main general approaches of in vivo cancer Analogous to other solid tumors, four main general approaches of in vivo cancer modeling can be distinguished for pediatric sarcoma (Figure 2) [12,13]. Two of these entail modeling can be distinguished for pediatric sarcoma (Figure2)[ 12,13]. Two of these entail the engraftment of human cancer tissue into immunocompromised mice—cell-line-de- the engraftment of human cancer tissue into immunocompromised mice—cell-line-derived rived xenograft models (CDXs) and patient-derived xenograft models (PDXs)—while the xenograft models (CDXs) and patient-derived xenograft models (PDXs)—while the other other two induce de novo tumorigenesis in immunocompetent wild type mice—environ- two induce de novo tumorigenesis in immunocompetent wild type mice—environmentally- mentally-induced models (EIMMs) and genetically-engineered mouse models (GEMMs). induced models (EIMMs) and genetically-engineered mouse models (GEMMs). Figure3 Figure 3 highlights the major advantages and disadvantages of these approaches. Inde- highlights the major advantages and disadvantages of these approaches. Independent of pendent of the specific approach, one should consider that different mouse strains, much the specific approach, one should consider that different mouse strains, much like humans, possesslike humans, an inherent possess and an inherent strain-specific and strain-specific risk of spontaneously risk of spontaneously developing differentdeveloping cancer dif- ferententities cancer over theirentities lifespans over their [14 lifespans,15]. While [14,15]. these While can, in these some can, cases, in some also cases, serve also as useful serve asmodels useful of models human of cancer, human they cancer, should they by should no means by no be mistakenmeans be formistaken specifically for specifically engrafted engraftedhuman or human induced or murine induced tumor murine tissue tumor [16]. tissue [16]. CDXs are the most commonly used, but least representative model when aiming to recapitulate the original disease. EIMMs are extremely powerful, but since pediatric sar- J. Clin. Med. 2021, 10, x FOR PEER REVIEW 3 of 27 comas are usually not driven by environmental factors, they are not as relevant for child- J. Clin. Med. 2021, 10, 1578 hood sarcoma. PDXs and GEMMs however, are highly representative of their human3 of 27 counterpart, therapeutically predictive and complementary to each other in nature. FigureFigure 2. 2. DifferentDifferent approaches approaches to tomodel model sarcoma sarcoma in vivo.in vivo Relative. Relative sizes sizes of mouse of mouse pictograms pictograms resemble resemble approximate approximate utili- zationutilization of modeling of modeling approaches approaches in current in current sarcoma sarcoma research. research. Dashed Dashed line illustrates line illustrates that environmentally-induced that environmentally-induced models (EIMMs)models (EIMMs) are typically are typically not particularly not particularly relevant relevantfor childhood for childhood sarcoma. sarcoma. 2.1. Genetically-EngineeredCDXs are the most commonlyMouse Models used, (GEMMs) but least representative model when aiming to recapitulateGEM models the follow original the disease. principle EIMMs of activating are extremely or inactivating powerful, specific but sincecancer-associ- pediatric atedsarcomas