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PMC12852540 | Choosing the right animal model for sarcoma research | Although humanised PDX models aim to overcome this limitation by incorporating human immune cells, they are technically demanding, expensive, and prone to complications, such as graft-versus-host disease. |
PMC12852540 | Choosing the right animal model for sarcoma research | Another challenge is the gradual replacement of human stromal and vascular components with murine equivalents during tumour growth, which can alter the response to treatments that target the tumour microenvironment, such as VEGF inhibitors in angiosarcoma or therapies that target hypoxic pathways in leiomyosarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | Furthermore, PDX models are less effective in studying metastasis because they often fail to replicate sarcoma-specific metastatic patterns, such as pulmonary spread in osteosarcoma or abdominal spread in liposarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | Serial passaging can also lead to clonal selection and genetic drift, resulting in tumours that diverge from the original patient’s biology. |
PMC12852540 | Choosing the right animal model for sarcoma research | Despite these limitations, PDX models remain an indispensable tool for preclinical research, especially when integrated with advanced technologies such as CRISPR-based gene editing, multi-omics profiling, and live imaging, or when used in combination with complementary systems such as organoids or genetically engineered mouse models (GEMMs), to provide a more comprehensive understanding of sarcoma biology and treatment. |
PMC12852540 | Choosing the right animal model for sarcoma research | Several tools are available to help identify the most appropriate PDX models, including resources such as Cancer Models (caMOD). |
PMC12852540 | Choosing the right animal model for sarcoma research | Table 1 provides an overview of the PDX models that have been used in published research. |
PMC12852540 | Choosing the right animal model for sarcoma research | However, many sarcoma subtypes still lack appropriate models. |
PMC12852540 | Choosing the right animal model for sarcoma research | To address this gap, Table 2 highlights the latest advances in PDX models for sarcoma research presented over the last three years at the largest sarcoma-focused conference, CTOS. |
PMC12852540 | Choosing the right animal model for sarcoma research | Table 1Patient-derived xenograft(PDX) models and their characteristics in sarcoma research Sarcoma Subtype Model ID Institution Tumour Type Patient age References OsteosarcomaOS55-SBXMDAnderson-CCHPrimaryND OS46-AOXMDAnderson-CCHPrimaryND OS47-SJMDAnderson-CCHPrimaryND OS49-STTXscMDAnderson-CCHPrimaryND OS45-TSXpr1MDAnderson-CCHPrimaryND OS49-SJMDAnderson-CCHPrimaryND OS50-SJMDAnderson-CCHRecurrentND NCH-OS1MDAnderson-CCHPrimaryND OS52-SJMDAnderson-CCHPrimaryND OS54-SJMDAnderson-CCHPrimaryND OS46MDAnderson-CCHPrimaryND OS54-OHSxMDAnderson-CCHPrimaryND OS44-KPDXxMDAnderson-CCHPrimaryND OS55MDAnderson-CCHNDND OS51-CHLXMDAnderson-CCHRefractoryND Breast RhabdomyosarcomaSJRHB046156_X1SJCRHRecurrent10–19 SJRHB046156_X2SJCRHRecurrent10–19 SJRHB030550_X1SJCRHRecurrent10–19 Bladder RhabdomyosarcomaSJRHB012_ZSJCRHRecurrent10–19 SJRHB063825_X1SJCRHRecurrent2–9 Malignant Mixed Mesodermal (Mullerian) Tumour*PMLB2865PMLBRecurrent70–79 NIBRX-4579DFCI-CPDMND40–49 NIBRX-3766DFCI-CPDMND50–59 NIBRX-4139DFCI-CPDMND60–69 NIBRX-2793DFCI-CPDMND70–79 NIBRX-4412DFCI-CPDMND60–69 NIBRX-2880DFCI-CPDMND70–79 NIBRX-3682DFCI-CPDMND30–39 NIBRX-3931DFCI-CPDMND60–69 *- tumour of mixed origin Patient-derived xenograft(PDX) models and their characteristics in sarcoma research *- tumour of mixed origin A search was conducted on the Mouse Models of Human Cancer Database (MMHCdb) using the following terms: The following terms were entered into Mouse Models of Human Cancer Database (MMHCdb) search engine: advanced sarcoma, advanced soft tissue sarcoma, alveolar rhabdomyosarcoma, biphasic synovial sarcoma, atypical lipomatous tumour/well-differentiated liposarcoma, bladder rhabdomyosarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | The following terms were entered into the database: bladder sarcoma, bone osteosarcoma, bone sarcoma, breast rhabdomyosarcoma, breast sarcoma, carcinosarcoma, cervical carcinosarcoma, and childhood epithelioid sarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | The search was refined to encompass PDX and other in vivo models, with cell lines excluded to prioritise more sophisticated and representative murine models in cancer research. |
PMC12852540 | Choosing the right animal model for sarcoma research | Furthermore, the filter for publications was employed. |
PMC12852540 | Choosing the right animal model for sarcoma research | Table 2Summary of sarcoma studies using Patient- derived xenograft presented at the CTOS conference over the last three yearsStudySarcoma subtypeModel descriptionFindingsZhang et al. Soft Tissue Sarcomas (STS)Xenograft models testing doxorubicin and panobinostat (HDAC inhibitor) in epithelial sarcoma and leiomyosarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | Combination therapy effective in epithelial sarcoma but ineffective in uterine leiomyosarcoma. |
PMC12852540 | Choosing the right animal model for sarcoma research | Zuco et al. Desmoplastic Small Round Cell Tumor (DSRCT)PDX model derived from a patient with EWSR1-WT1 fusion-positive DSRCT, evaluating irinotecan-based therapies. |
PMC12852540 | Choosing the right animal model for sarcoma research | Irinotecan-trabectedin combination induced complete tumor regression, demonstrating translational potential. |
PMC12852540 | Choosing the right animal model for sarcoma research | Stacchiotti et al. Epithelioid Hemangioendothelioma (EHE)PDX model of EHE with fusion genes, tested for therapeutic efficacy of sirolimus and doxorubicin. |
PMC12852540 | Choosing the right animal model for sarcoma research | Sirolimus significantly reduced tumour growth through mTOR inhibition, validating its use in the treatment of EHE.Wozniak et al. Various STS SubtypesEstablished 76 PDX models from various STS subtypes, maintaining molecular and histological features of original tumors. |
PMC12852540 | Choosing the right animal model for sarcoma research | PDX models faithfully represented 17 STS subtypes, enabling precise preclinical drug testing. |
PMC12852540 | Choosing the right animal model for sarcoma research | Danieau et al. Osteosarcoma (OS)PDX models of recurrent and metastatic OS; used MAP chemotherapy to evaluate treatment efficacy and metastatic behavior. |
PMC12852540 | Choosing the right animal model for sarcoma research | MAP chemotherapy controlled primary OS tumors but failed to prevent metastasis; chemoresistant metastatic models generated for further study. |
PMC12852540 | Choosing the right animal model for sarcoma research | Danieau et al. OSSecond OS study exploring the role of tumor microenvironment and epigenetic factors influencing chemoresistance and metastasis in PDX models. |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumor microenvironment studies revealed stromal contributions to resistance; epigenetic regulators as potential therapeutic targets identified. |
PMC12852540 | Choosing the right animal model for sarcoma research | De Sutter et al. Gastrointestinal Stromal Tumor (GIST)Established 12 PDX models of GIST with varied KIT and PDGFRA mutations to evaluate tyrosine kinase inhibitors (TKIs).PDX models replicated GIST histological features and were used for preclinical drug testing, including imatinib-resistant cases. |
PMC12852540 | Choosing the right animal model for sarcoma research | Kozinova et al. GISTSix GIST PDX models derived from refractory cases with KIT/PDGFRA mutations, tested for Wee1 inhibitor and sunitinib efficacy. |
PMC12852540 | Choosing the right animal model for sarcoma research | Wee1 inhibitor combined with sunitinib showed significant growth inhibition in polyclonal GIST tumors, highlighting therapeutic potential. |
PMC12852540 | Choosing the right animal model for sarcoma research | Gordon et al. Rhabdomyosarcoma (RMS)36 orthotopic PDX models of RMS, representing embryonal, alveolar, and sclerosing subtypes; tested ATR/WEE1 inhibitors with irinotecan combinations. |
PMC12852540 | Choosing the right animal model for sarcoma research | ATR/WEE1 inhibitors with irinotecan enhanced survival in most RMS PDXs; twin-mouse design improved experimental robustness. |
PMC12852540 | Choosing the right animal model for sarcoma research | De Cock et al. Synovial Sarcoma (SS)SS PDX treated with YAP1 inhibitor (verteporfin) and pazopanib combination. |
PMC12852540 | Choosing the right animal model for sarcoma research | Combination stabilized tumors but was poorly tolerated; apoptosis and reduced mitosis observed. |
PMC12852540 | Choosing the right animal model for sarcoma research | Gijsels et al. Malignant Peripheral Nerve Sheath TumorMRD-PDX developed from paired primary, recurrent, and metastatic patient tumors. |
PMC12852540 | Choosing the right animal model for sarcoma research | Revealed intratumoral and metastatic heterogeneity; docetaxel suppressed metastatic kidney and lung tumor growth. |
PMC12852540 | Choosing the right animal model for sarcoma research | Gorgels et al. STSPDX models of LMS, DDLPS, and CIC-rearranged sarcoma treated with ecubectedin and PM54 to assess tumor growth and histology. |
PMC12852540 | Choosing the right animal model for sarcoma research | Ecubectedin and PM54 significantly reduced tumor volume, induced apoptosis, and outperformed standard chemotherapy in most models. |
PMC12852540 | Choosing the right animal model for sarcoma research | Lewandowski et al. VariousPDX models testing anti-EDB + FN antibody-drug conjugate PYX-201 across multiple sarcoma subtypes, analyzing tumor response and EDB + FN expression. |
PMC12852540 | Choosing the right animal model for sarcoma research | YX-201 demonstrated strong to very strong anti-tumor activity in over 50% of tested sarcoma PDX models, with a specific focus on stroma targeting. |
PMC12852540 | Choosing the right animal model for sarcoma research | Summary of sarcoma studies using Patient- derived xenograft presented at the CTOS conference over the last three years While traditional PDX models are excellent at recapitulating the genetic, histological and molecular characteristics of tumours, they lack a functional human immune system, which is critical for studying immuno-oncology therapies and tumour-immune interactions . |
PMC12852540 | Choosing the right animal model for sarcoma research | To overcome this limitation, humanised (hu)PDX models have been developed by engrafting immunodeficient mice such as NSG (NOD/SCID IL2rγ chain knockout) mice with human immune components, such as peripheral blood mononuclear cells (PBMCs) or haematopoietic stem cells (HSCs), followed by implantation of patient-derived tumours . |
PMC12852540 | Choosing the right animal model for sarcoma research | This dual engraftment creates a system in which human tumours interact with a functional human immune system, enabling the study of immune checkpoint inhibitors, T-cell therapies and immune-related resistance mechanisms. |
PMC12852540 | Choosing the right animal model for sarcoma research | The process of developing a humanised PDX models is presented in Fig. 1. |
PMC12852540 | Choosing the right animal model for sarcoma research | For instance, De Wispelaere et al. employed a huPDX model to investigate the potential of combined PI3K/mTOR inhibitors and PD-1 blockade for treating uterine leiomyosarcoma (uLMS), a type with poor immune responsiveness. |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumour growth and therapeutic responses were closely monitored over time. |
PMC12852540 | Choosing the right animal model for sarcoma research | The tumour-bearing mice were treated with a PI3Kα inhibitor (alpelisib) and a mTORC1/2 inhibitor (sapanisertib), either as single agents or in combination with nivolumab (anti-PD-1 therapy). |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumour volumes were measured and detailed analyses were performed using immunohistochemistry, single-cell RNA sequencing and T-cell receptor (TCR) profiling. |
PMC12852540 | Choosing the right animal model for sarcoma research | To further investigate the immune landscape, multiplex immunofluorescence and single-cell transcriptomics were used to assess immune cell infiltration, T-cell status and macrophage polarisation within the tumour microenvironment. |
PMC12852540 | Choosing the right animal model for sarcoma research | TCR sequencing provided insight into clonal T cell expansion and differentiation. |
PMC12852540 | Choosing the right animal model for sarcoma research | The combination of PI3K/mTOR inhibitors with PD-1 blockade significantly enhanced CD4 + Th1 and CD8 + effector T cell infiltration. |
PMC12852540 | Choosing the right animal model for sarcoma research | Treated tumours exhibited reduced T-cell exhaustion and increased cytotoxic activity, effectively reversing the immunosuppressive tumour microenvironment. |
PMC12852540 | Choosing the right animal model for sarcoma research | While single-agent PD-1 blockade alone had minimal effect, the combination therapy produced partial responses in 90% of cases, including one complete response. |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, PI3K/mTOR inhibition repolarised macrophages towards an anti-tumorigenic (M1-like) phenotype and enhanced dendritic cell-mediated antigen presentation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Comparisons with non-humanised mice underscored the critical role of the human immune system in tumour control during combination therapy, highlighting the enhanced efficacy of these approaches in a human-relevant immunological context. |
PMC12852540 | Choosing the right animal model for sarcoma research | Fig. 1Process of developing humanized PDX models for sarcoma research Process of developing humanized PDX models for sarcoma research In addition to these benefits, the major drawback is the use of a xenograft-versus-host disease (xGvHD that instals a few weeks after PBMCs inoculation, and it is believed to be associated with major histocompatibility complex (MHC) divergences between human and mouse T cells . |
PMC12852540 | Choosing the right animal model for sarcoma research | In particular, NSG (NOD-scid IL2rγ-/-) mice, which allows engraftment of human immune cells, are widely used to study human immune responses and cancer interactions because of their immunodeficiency. |
PMC12852540 | Choosing the right animal model for sarcoma research | However, transplantation of human PBMCs often results in xenogeneic GvHD, in which human T cells attack mouse tissues, mirroring the pathology of GvHD in haematopoietic stem cell transplantation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Before PBMC transplantation, bone marrow destruction by total body irradiation (TBI) is a critical preparatory step. |
PMC12852540 | Choosing the right animal model for sarcoma research | TBI eliminates residual mouse haematopoietic cells, creating space for human cell engraftment and reducing immune resistance. |
PMC12852540 | Choosing the right animal model for sarcoma research | While this improves human cell engraftment, there are challenges, including variability in irradiation protocols, which can lead to inconsistent proportions of human cells and differences in GvHD severity . |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, the cytokine storm induced by irradiation can mimic inflammatory conditions, complicating the interpretation of immune response data. |
PMC12852540 | Choosing the right animal model for sarcoma research | Xenogeneic GvHD is primarily driven by human T cells that expand and differentiate after stimulation by mouse antigen presenting cells (APCs) .Mouse dendritic cells and macrophages present antigens via MHC molecules that activate human CD4 + and CD8 + T cells These activated T cells proliferate and infiltrate various organs, causing tissue damage through the secretion of cytokines such as IFN-γ and TNF-α and direct cytotoxicity . |
PMC12852540 | Choosing the right animal model for sarcoma research | In humanised mice, GvHD typically manifests as weight loss, anaemia and impaired mobility. |
PMC12852540 | Choosing the right animal model for sarcoma research | However, some hallmark symptoms of human GvHD, such as diarrhoea and rash, are less commonly observed, indicating that these models only partially recapitulate the human condition. |
PMC12852540 | Choosing the right animal model for sarcoma research | NSG mice lack human compatible cytokines such as IL-7 and IL-15, which are essential for the maintenance of human NK and myeloid cells . |
PMC12852540 | Choosing the right animal model for sarcoma research | This limitation reduces the ability of the model to reproduce the full spectrum of human immune responses. |
PMC12852540 | Choosing the right animal model for sarcoma research | In addition, the absence of lymph nodes and reduced thymic function in NSG mice affects the activation and differentiation of human T cells, which rely heavily on the spleen and bone marrow niche for priming. |
PMC12852540 | Choosing the right animal model for sarcoma research | The genetic heterogeneity of PBMC donors also contributes to variability in disease dynamics, reflecting the diversity observed in human populations. |
PMC12852540 | Choosing the right animal model for sarcoma research | The primary advantage of huPDX models is their ability to retain the genetic and phenotypic complexity of human sarcomas while incorporating a functional human immune system. |
PMC12852540 | Choosing the right animal model for sarcoma research | These models combine the strengths of traditional PDX models, which retain the heterogeneity of the original tumour, with the immunological relevance of humanised mice . |
PMC12852540 | Choosing the right animal model for sarcoma research | By transplanting human haematopoietic stem cells (HSCs) into immunodeficient mouse strains such as NOD/SCID or NSG , researchers can recapitulate critical tumour-immune interactions, making humanised PDX models particularly suitable for immunotherapy studies . |
PMC12852540 | Choosing the right animal model for sarcoma research | These models preserve the genetic diversity of complex sarcomas such as leiomyosarcoma or undifferentiated pleomorphic sarcoma (UPS), which often exhibit widespread chromosomal instability. |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, dedifferentiated liposarcoma (DDLPS) PDX models retain key genomic amplifications in MDM2 and CDK4 and, when humanised, allow detailed analysis of the tumour microenvironment (TME) . |
PMC12852540 | Choosing the right animal model for sarcoma research | This is critical for understanding the interplay between sarcoma cells and immune components such as tumour-associated macrophages (TAMs) or regulatory T cells (Tregs), which drive immunosuppression and therapy resistance . |
PMC12852540 | Choosing the right animal model for sarcoma research | HuPDX models are invaluable for evaluating immunotherapies such as immune checkpoint inhibitors or chimeric antigen receptor (CAR) T-cell therapies . |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, in Ewing sarcoma, a fusion-driven subtype, humanised models have shown how tumours evade immune detection through mechanisms such as PD-L1 upregulation. |
PMC12852540 | Choosing the right animal model for sarcoma research | These models allow researchers to test anti-PD-1 or anti-CTLA-4 therapies in a controlled environment and to see their effects on T-cell activation and tumour regression. |
PMC12852540 | Choosing the right animal model for sarcoma research | Similarly, in alveolar rhabdomyosarcoma (ARMS), huPDX models have been used to study CAR-T cells targeting the PAX3-FOXO1 fusion protein, highlighting how immunosuppressive pathways in the TME can influence treatment outcomes. |
PMC12852540 | Choosing the right animal model for sarcoma research | Another important application is the study of resistance mechanisms to immunotherapies and targeted treatments. |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, in leiomyosarcoma, huPDX models have revealed how tumours that initially respond to anti-PD-1 therapy can develop resistance by upregulating alternative immune checkpoints such as TIM-3 or LAG-3 . |
PMC12852540 | Choosing the right animal model for sarcoma research | These findings are informing combination therapy strategies, such as combining checkpoint inhibitors with epigenetic modulators or cytokine therapies, to overcome resistance. |
PMC12852540 | Choosing the right animal model for sarcoma research | The primary limitation is that they are time-consuming, costly, and technically demanding to establish, as human hematopoietic stem cells must be engrafted into immunodeficient mice over several months to recreate a functional human immune system. |
PMC12852540 | Choosing the right animal model for sarcoma research | The establishment of huPDX is characterised by two rate-limiting intervals: human immune reconstitution and primary tumour growth. |
PMC12852540 | Choosing the right animal model for sarcoma research | These typically take 18–24 weeks before treatment readiness. |
PMC12852540 | Choosing the right animal model for sarcoma research | In hu-HSC or BLT settings, human CD45+ (hCD45+) cells become detectable in the peripheral blood by weeks 4–6. |
PMC12852540 | Choosing the right animal model for sarcoma research | Systemic immune reconstitution reaches study-ready levels by approximately weeks 10–12 and continues to mature thereafter. |
PMC12852540 | Choosing the right animal model for sarcoma research | A practical window for T-cell-centric studies is often 14–16 weeks post-humanisation, depending on the strain and conditioning . |
PMC12852540 | Choosing the right animal model for sarcoma research | Tumour engraftment from fresh surgical material to a measurable F1 xenograft generally requires a further 2–4 months, with failure declared if no growth is observed by 6 months. |
PMC12852540 | Choosing the right animal model for sarcoma research | Subsequent passaging to study cohorts adds additional weeks, but this is shorter than the initial engraftment period .Taken together, a conservative scheduling assumption for huPDX efficacy studies is 20–28 weeks from the receipt of tumour tissue and human cells to the first dose, depending on the histotype of the disease, the mouse strain, and the humanisation strategy . |
PMC12852540 | Choosing the right animal model for sarcoma research | This process often shows variable immune cell reconstitution, restricting the reliability of immune-related studies . |
PMC12852540 | Choosing the right animal model for sarcoma research | Although these models incorporate a human immune system, the immune cells are usually derived from donor HSCs rather than the patient from whom the tumour was derived . |
PMC12852540 | Choosing the right animal model for sarcoma research | This mismatch can fail to replicate the unique tumour-immune dynamics present in individual patients. |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, leiomyosarcomas often exhibit immune evasion strategies tailored to the patient environment, such as the recruitment of regulatory T cells (Tregs) or M2-polarised macrophages, which may not be fully captured in a non-patient-specific mode . |
PMC12852540 | Choosing the right animal model for sarcoma research | HuPDX models also suffer from incomplete cytokine signalling pathways . |
PMC12852540 | Choosing the right animal model for sarcoma research | Mouse stroma and tissue environments differ from human counterparts, and certain cytokines critical for immune cell function, such as interleukin-7 (IL-7) or interleukin-15 (IL-15), are not efficiently cross-reactive between species . |
PMC12852540 | Choosing the right animal model for sarcoma research | This can affect the survival, proliferation and activity of human immune cells such as CD8 + cytotoxic T cells or NK cells. |
PMC12852540 | Choosing the right animal model for sarcoma research | For example, in studies of immune checkpoint inhibitors targeting PD-1 or CTLA-4 in sarcomas, the lack of robust cytokine signalling may lead to underestimation of therapeutic potential or biased results regarding immune activation. |
PMC12852540 | Choosing the right animal model for sarcoma research | Moreover, these models have incomplete human cytokine networks due to species-specific differences in signaling molecules, which can reduce the survival and function of key immune cells and bias interpretations of immunotherapy efficacy. |
PMC12852540 | Choosing the right animal model for sarcoma research | Additional drawbacks include high maintenance costs, limited model scalability—particularly for rare sarcomas—and a short mouse lifespan that constrains long-term studies of tumor dormancy and late metastasis. |
PMC12852540 | Choosing the right animal model for sarcoma research | Variable tumor engraftment, growth, and structural fidelity further challenge the accurate assessment of therapies such as anti-angiogenic treatments. |
PMC12852540 | Choosing the right animal model for sarcoma research | Despite these issues, huPDX models remain valuable for examining immunotherapeutic strategies against sarcomas. |
PMC12852540 | Choosing the right animal model for sarcoma research | Improvements in immune reconstitution methods, cytokine supplementation, and the development of longer-lived host strains may enhance their applicability and reliability in future preclinical research. |
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