A guide to preclinical model selection in sarcoma research: factors and tools to consider

What is it about?

The most commonly used models are: syngeneic, genetically engineered mouse (GEM), chemically induced, cell-derived xenografts (CDX), patient-derived xenografts (PDX), humanised PDX (huPDX), and zebrafish. Each model has its own advantages, for example: CDXs enable high-throughput drug screening, PDXs preserve tumour heterogeneity in patients, while huPDXs most closely resemble the human immune response, However, there are various limitations to each model, including a lack of genetic diversity in syngeneic models, the complexity and time requirements of GEMs, and the short life span of cost-effective zebrafish. We also described various tools that can be used to help select the right animal model.

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Photo by National Cancer Institute on Unsplash

Photo by National Cancer Institute on Unsplash

Why is it important?

Choosing the right animal model is in very complex and requires the consideration of multiple factors. Some rare sarcoma types, owing to their rarity and complex molecular drivers, such as clear cell sarcoma and alveolar soft part sarcoma, present significant challenges for developing relevant models. Collaborative efforts, such as international sarcoma networks and biobank initiatives, are essential to pool resources to develop and validate models for these subtypes. In addition, understanding the metastatic behaviour of sarcomas, particularly their predilection for lung metastases, requires refined models that recapitulate the specific tumour microenvironment, including hypoxia and angiogenesis. The role of signalling pathways such as p53, Rb, PI3K/AKT and Wnt in driving sarcomagenesis and the contribution of epigenetic alterations mediated by fusion oncoproteins such as EWS-FLI1 and SS18-SSX must also be considered in model selection. Recent studies using GEMMs and PDX models have identified therapeutic vulnerabilities, such as the dependence on oxidative phosphorylation in YAP1-driven sarcomas, which could be exploited with combination therapies. Multiple tools can help with the selection, including International Mouse Strain Resource and Rat Genome Database. Our review also comes with limitations; it primarily summarises existing preclinical studies and methodological descriptions, with limited quantitative synthesis (e.g., meta-analysis or systematic scoring of model fidelity or translational success) included. Furthermore, the paper notes that many sarcoma models fail to fully capture the genetic and immunological complexity of human tumours, particularly ultra-rare or fusion-driven subtypes. Some models, such as chemically induced sarcomas or CDX, have limited clinical relevance due to the artificial evolution of tumours or the lack of interactions with the immune system.

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