Orthotopic model of pancreatic cancer using CD34+ humanized mice and generation of tumor organoids from humanized tumors

Jeong, Ji Hye; Park, Su‐Jin; Lee, Sang Yeon; Kim, Yeounhee; Shim, In Kyong; Jeong, Seong-Yun; Choi, Eun Kyung; Kim, Jinju; Jun, Eunsung

doi:10.1016/j.intimp.2023.110451

Cited by 3 publications

(2 citation statements)

References 41 publications

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“…Orthotopic xenografts can offer a more accurate representation of the metastatic behavior of tumors and their TME [42, 43]. Previous studies have explored the development of orthotopic xenograft models in Hu-mice, using luciferase-positive human pancreatic and osteosarcoma cells [44, 45]. The orthotopic OC xenograft model in Hu-mice, using the OV-90 luciferase cell line and PDX cells, was initially employed to verify the response to nivolumab [19].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Profiling and Characterization of Peritoneal Metastasis Ovarian Cancer Xenografts in Humanized Mice

Kang,

Lee,

Kang

et al. 2023

Preprint

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BackgroundAlthough immunotherapy has not yet been as successful in ovarian cancer (OC), it remains a potential therapeutic strategy. Preclinical models of OC are necessary to evaluate the efficacy of immuno-oncology (IO) drugs targeting human cancer and immune components but have been underutilized. Developing mouse models with a humanized (Hu) immune system can help understand the human immune response to IO drugs, including immune checkpoint inhibitors (ICIs), which have demonstrated limited effectiveness in OC patients.MethodsWe established OC xenograft Hu-mouse models by intraperitoneally injecting luciferase-expressing SKOV-3 Luc and OVCAR-3 Luc OC cells into CD34+Hu-mice. Tumor growth was monitored through bioluminescence imaging (BLI). We assessed the efficacy of PD-1 blockade with pembrolizumab in the SKOV-3 Luc Hu-mouse model. The immune profiles of the tumors were characterized using colorimetric immunostaining and flow cytometry. Additionally, we analyzed RNA-seq data to investigate the gene expression signature of pembrolizumab refractory tumors.ResultsWe confirmed tumor development in both OC cell lines within CD34+Hu-mice. In these models, human lymphocyte and myeloid cell subsets were present in the tumors, draining lymph nodes, blood, and spleens. The SKOV-3 Luc tumor-bearing Hu-mice did not respond to pembrolizumab monotherapy. These tumors exhibited a high presence of tumor-infiltrating macrophages. Tumors in Hu-mice unresponsive to pembrolizumab showed a lower abundance of CD8+T-cells, memory B cells, plasma cells, and a higher proportion of naïve M0 macrophages and mast cells compared to the PBS control. Furthermore, we identified 43 significantly enriched gene sets in these tumors. The differentially expressed genes (DEGs) were predominantly enriched in HDAC class I, RB1, KLF1/3, TCF21, MYD88, SMARCE1 target genes, and genes associated with epithelial-mesenchymal transition (EMT) and fibroblasts.ConclusionOur xenograft Hu-mouse model of OC provides a valuable tool for investigating the efficacy of IO drugs. The insights gained from this model offer potential avenues to explore mechanisms of resistance to PD-1/PD-L1 blockade in OC.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Profiling and Characterization of Peritoneal Metastasis Ovarian Cancer Xenografts in Humanized Mice

Kang,

Lee,

Kang

et al. 2023

Preprint

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“…| (2024) 14:11894 | https://doi.org/10.1038/s41598-024-60501-z www.nature.com/scientificreports/ models in Hu-mice, using luciferase-positive human pancreatic and osteosarcoma cells 46,47 . The orthotopic OC xenograft model in Hu-mice, using the OV-90 luciferase cell line and PDX cells, was initially employed to verify the response to nivolumab 19 .…”

Section: Scientific Reportsmentioning

confidence: 99%

Transcriptome profiling and characterization of peritoneal metastasis ovarian cancer xenografts in humanized mice

Kang,

Lee,

Kang

et al. 2024

Sci Rep

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Although immunotherapy has not yet been as successful in ovarian cancer (OC), it remains a potential therapeutic strategy. Preclinical models of OC are necessary to evaluate the efficacy of immuno-oncology (IO) drugs targeting human immune components but have been underutilized. Developing mouse models with a humanized (Hu) immune system can help understand the human immune response to IO drugs which have demonstrated limited effectiveness in OC patients. We established OC xenograft Hu-mouse models by intraperitoneally injecting luciferase-expressing SKOV-3 Luc and OVCAR-3 Luc OC cells into CD34+ Hu-mice. Tumor growth was monitored through bioluminescence imaging (BLI). In the SKOV-3 Luc Hu-mouse model, we assessed the efficacy of PD-1 blockade with pembrolizumab. We observed the presence of human lymphocyte and myeloid cell subsets within the tumors, lymph nodes, blood, and spleens in these models. Notably, these tumors exhibited a high prevalence of tumor-infiltrating macrophages. Furthermore, we identified HDAC class I target genes, and genes associated with epithelial-mesenchymal transition (EMT) and fibroblasts in the tumors of Hu-mice treated with pembrolizumab. Our xenograft Hu-mouse model of OC provides a valuable tool for investigating the efficacy of IO drugs. The insights gained from this model offer useful information to explore potential mechanisms associated with unresponsive anti-PD-1 treatment in OC.

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Modelling the micro- and macro- environment of pancreatic cancer: from patients to pre-clinical models and back

Lloyd,

Henríquez,

Biffi

2024

Disease Models &Amp; Mechanisms

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with very low survival rates. Over the past 50 years, improvements in PDAC survival have significantly lagged behind the progress made in other cancers. PDAC’s dismal prognosis is due to typical late-stage diagnosis combined with lack of effective treatments and complex mechanisms of disease. We propose that improvements in survival are partly hindered by the current focus on largely modelling and targeting PDAC as one disease, despite it being heterogeneous. Implementing new disease-representative pre-clinical mouse models that capture this complexity could enable the development of transformative therapies. Specifically, these models should recapitulate human PDAC late-stage biology, heterogeneous genetics, extensive non-malignant stroma, and associated risk factors and comorbidities. In this Perspective, we focus on how pre-clinical mouse models could be improved to exemplify key features of PDAC micro- and macro- environments, which would drive clinically relevant patient stratification, tailored treatments and improved survival.

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Orthotopic model of pancreatic cancer using CD34+ humanized mice and generation of tumor organoids from humanized tumors

Cited by 3 publications

References 41 publications

Transcriptome Profiling and Characterization of Peritoneal Metastasis Ovarian Cancer Xenografts in Humanized Mice

Transcriptome Profiling and Characterization of Peritoneal Metastasis Ovarian Cancer Xenografts in Humanized Mice

Transcriptome profiling and characterization of peritoneal metastasis ovarian cancer xenografts in humanized mice

Modelling the micro- and macro- environment of pancreatic cancer: from patients to pre-clinical models and back

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