A Novel Humanized Immune Stroma PDX Model for Therapeutic Studies
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PROVIDER: PRJNA923347 | ENA |
REPOSITORIES: ENA
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Project description:Standard preclinical human tumor models lack a human tumor stroma. However, as stroma contributes to therapeutic resistance, the lack of human stroma may make current models less stringent for testing new therapies. To address this, we created a human in mouse model of cancer with a human tumor stroma. This humanized immune stroma patient derived xenograft (HIS-PDX) uses patient-derived tumor cells, cancer-associated mesenchymal stem cells and human endothelial cells transplanted into BLT (bone marrow, liver, thymus) humanized mice. The model contains human connective tissues, vascular and immune cell infiltrates. RNA sequencing analysis demonstrated a 94-96% correlation with primary human tumor. Using this model, we demonstrate the impact of human tumor stroma on response to both small molecule and immune therapies. Combined our data confirm a critical role for human stoma plays an important role in therapeutic response and that this model can be an important tool for preclinical drug testing.
2024-12-31 | GSE222774 | GEO
Project description:In solid tumors, the exhaustion of natural killer (NK) cells and cytotoxic T cells in the immunosuppressive tumor microenvironment poses challenges for effective tumor control. Conventional humanized mouse models of hepatocellular carcinoma-patient-derived xenografts (HCC-PDX) encounter limitations in NK-cell infiltration, hindering studies on NK-cell immunobiology. Here, we introduce an improved humanized mouse model with restored NK-cell reconstitution and infiltration in HCC-PDX, coupled with single-cell RNA-sequencing (scRNA-seq) to identify potential anti-HCC treatments. A single administration of adeno-associated virus carrying human interleukin-15 (AAV-hIL15) reinstated persistent NK-cell reconstitution and infiltration in HCC-PDX in humanized mice. ScRNA-seq revealed exhausted NK-cell and T-cell subpopulations with heightened PDCD1 and TIGIT levels. Notably, combination therapy with anti-PD-1 and anti-TIGIT antibodies alleviated HCC burden in humanized mice, demonstrating NK cell-dependent efficacy. Bulk-RNA sequencing analysis also revealed significant alterations in the tumor transcriptome that may contribute to further resistance after combination therapy, warranting further investigations. As an emerging strategy, ongoing clinical trials with anti-PD-1 and anti-TIGIT antibodies provide limited data. The improved humanized mouse HCC-PDX model not only sheds light on the pivotal role of NK cells but also serves as a robust platform for evaluating safety and anti-tumor efficacy of combination therapies and other potential regimens, complementing clinical insights.
2024-12-28 | GSE265770 | GEO
Project description:In solid tumors, the exhaustion of natural killer (NK) cells and cytotoxic T cells in the immunosuppressive tumor microenvironment poses challenges for effective tumor control. Conventional humanized mouse models of hepatocellular carcinoma-patient-derived xenografts (HCC-PDX) encounter limitations in NK-cell infiltration, hindering studies on NK-cell immunobiology. Here, we introduce an improved humanized mouse model with restored NK-cell reconstitution and infiltration in HCC-PDX, coupled with single-cell RNA-sequencing (scRNA-seq) to identify potential anti-HCC treatments. A single administration of adeno-associated virus carrying human interleukin-15 (AAV-hIL15) reinstated persistent NK-cell reconstitution and infiltration in HCC-PDX in humanized mice. ScRNA-seq revealed exhausted NK-cell and T-cell subpopulations with heightened PDCD1 and TIGIT levels. Notably, combination therapy with anti-PD-1 and anti-TIGIT antibodies alleviated HCC burden in humanized mice, demonstrating NK cell-dependent efficacy. Bulk-RNA sequencing analysis also revealed significant alterations in the tumor transcriptome that may contribute to further resistance after combination therapy, warranting further investigations. As an emerging strategy, ongoing clinical trials with anti-PD-1 and anti-TIGIT antibodies provide limited data. The improved humanized mouse HCC-PDX model not only sheds light on the pivotal role of NK cells but also serves as a robust platform for evaluating safety and anti-tumor efficacy of combination therapies and other potential regimens, complementing clinical insights.
2024-12-28 | GSE265769 | GEO
Project description:Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small animal models. Here we demonstrate that IL-15 is a critical CTCL growth and survival factor. Importantly, a genetically engineered immunodeficient mouse model expressing human IL-15 uniquely supported the growth of patient derived Sezary cells relative to conventional immunodeficient mouse strains. Patient derived xenograft (PDX) SS models recapacitated the pathologic features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single cell transcriptome analysis revealed tissue specific regulation of gene expression and distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of the humanized IL-15, immunodeficient mice for SS PDX model generation. Furthermore, these studies advocate for the thorough molecular understanding of the resultant PDX models to maximize their translational impact.
2023-09-29 | GSE227326 | GEO
Project description:Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small animal models. Here we demonstrate that IL-15 is a critical CTCL growth and survival factor. Importantly, a genetically engineered immunodeficient mouse model expressing human IL-15 uniquely supported the growth of patient derived Sezary cells relative to conventional immunodeficient mouse strains. Patient derived xenograft (PDX) SS models recapacitated the pathologic features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single cell transcriptome analysis revealed tissue specific regulation of gene expression and distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of the humanized IL-15, immunodeficient mice for SS PDX model generation. Furthermore, these studies advocate for the thorough molecular understanding of the resultant PDX models to maximize their translational impact.
2023-09-29 | GSE229406 | GEO
Project description:Clinically relevant methods are not available that prioritize and validate potential therapeutic targets for individual tumors from the vast amount of tumor descriptive expression data. We established inducible transgene expression in clinically relevant patient-derived xenograft (PDX) models in vivo to fill this gap. With this technique at hand, we analyzed the role of the transcription factor Krüppel-like factor 4 (KLF4) in B-cell acute lymphoblastic leukemia (B-ALL) PDX models at different disease stages. In competitive preclinical in vivo trials, we found that re-expression of wild type KLF4 reduced the leukemia load in PDX models of B-ALL, with the strongest effects being observed after conventional chemotherapy in minimal residual disease (MRD). A nonfunctional KLF4 mutant had no effect on this model. The re-expression of KLF4 sensitized tumor cells in the PDX model towards systemic chemotherapy in vivo. It is of major translational relevance that azacitidine upregulated KLF4 levels in the PDX model and a KLF4 knockout reduced azacitidine-induced cell death, suggesting that azacitidine can regulate KLF4 re-expression. These results support the application of azacitidine in patients with B-ALL as a therapeutic option to regulate KLF4. Genetic engineering of PDX models allows the examination of the function of dysregulated genes like KLF4 in a highly clinically relevant translational context, and it also enables the selection of therapeutic targets in individual tumors and links their functions to clinically available drugs, which will facilitate personalized treatment in the future.
2020-06-27 | GSE153382 | GEO
Project description:Patient-derived xenograft (PDX) models are commonly used for preclinical evaluation of targeted therapies. It is important to consider the fidelity with which these systems recapitulate the patient disease state. Currently, there is little information regarding how well pediatric AML PDXs mimic the global gene expression found in patients. Here we analyzed RNAseq data from a diverse series of high-risk pediatric AML PDXs, separately and compared to primary patient data. Unsupervised clustering of PDX data resulted in segregation according to KMT2A (MLL) status. Combined analysis showed PDX samples aligned with patient samples harboring similar genetics. Among KMT2A rearranged samples, we observed strong correlation of expression levels of nearly all expressed transcripts. Furthermore, matched patient/PDX pairs showed strong concordance, suggesting retention of sample-specific gene expression. Interestingly, our analysis uncovered previously unidentified cryptic CBFA2T3-GLIS2 rearrangement in two PDX models. Based on high BCL2 mRNA in these models, we tested the efficacy of venetoclax in combination with chemotherapy. While standard daunorubicin/ara-C treatment failed to produce benefits, CPX-351 decreased disease burden and prolonged survival, particularly when combined with venetoclax. These results validate PDX modeling of high-risk pediatric AML and highlight this system's utility for pre-clinical therapeutic discovery, especially for rare subtypes of disease.
2025-01-09 | GSE252945 | GEO
Project description:Transcriptomes of the cancer (human) and stroma (mouse) of 70 PDX samples consisted of 9 distinctive tumor types were analyzed in this study to investigate to the tumor micro-environment (TME). PDX models recapitulated the features of the original tumors, including tumor-purity, stromal cell composition, and putative signaling. An integrated analysis was conducted to identify the upstream paracrine effectors that govern the stromal transcriptome in KIRC PDXs, which were confirmed by using the complementary cancer transcriptome based on the hypothesis that cancer-derived effectors which play key roles in the formation of the cancer-stroma communication should be upregulated in cancer cells.
2021-10-11 | GSE159702 | GEO
Project description:Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia [PDX shMFN2]
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