The Tie-2 antagonist rebastinib reduces ovarian cancer growth in a syngeneic murine model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE272411 | GEO | 2024/07/18
REPOSITORIES: GEO
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Project description:The Tie-2 antagonist rebastinib reduces ovarian cancer growth in a syngeneic murine model
| PRJNA1136832 | ENA
Project description:BackgroundThe receptor tyrosine kinase TIE2 and its ligands, angiopoietins (ANGPTs), promote angiogenesis. In addition to expression on vascular endothelial cells, TIE2 is expressed on M2-like pro-tumorigenic macrophages. Thus, the TIE2 inhibitor rebastinib was developed as a potential therapy to address multiple cancers. The objective of this study was to determine the effects of rebastinib alone and combined with chemotherapy in a syngeneic murine model of ovarian cancer.MethodsFemale C57Bl6J mice were intraperitoneally injected with syngeneic ID8 ovarian cancer cells. Once tumors were established, mice were untreated (control) or treated with rebastinib, carboplatin plus paclitaxel (chemotherapy), or rebastinib plus chemotherapy. In one set of experiments, survival was followed for 140 days. In other experiments, ascites was harvested 24 h after the last treatment and analyzed by flow cytometry. In in vitro experiments, RNA sequencing was performed on ID8 cells and murine peritoneal macrophage cells (PMJ2R) after treatment with rebastinib, chemotherapy, or rebastinib plus chemotherapy.ResultsTumor-bearing mice treated with rebastinib plus chemotherapy had longer median survival than mice treated with chemotherapy (132.5 vs. 127 days, P < 0.01). Ascites from mice treated with rebastinib had more CD45 + macrophages (P < 0.03) and cytotoxic T cells (P < 0.0001) than ascites from mice treated with chemotherapy. Rebastinib had no significant effect on the numbers of regulatory T cells, Tie2 + macrophages, or Tie2 + M2 macrophages. In ID8 cells, in vitro, rebastinib treatment upregulated 1528 genes and downregulated 3115 genes. In macrophages, in vitro, rebastinib treatment upregulated 2302 genes and downregulated 2970 genes. Rebastinib differentially regulated ANGPT-like proteins in both types of cells, including several ANGPT-like genes involved in tumorigenesis, angiogenesis, and proliferation. ANGPTL1, an anti-angiogenic and anti-apoptotic gene, was increased tenfold in ID8 cells treated with rebastinib (P < 0.001) but was not altered in macrophages.ConclusionsRebastinib plus chemotherapy extends survival in a syngeneic murine model of ovarian cancer. Rebastinib alters proportions of immune cell subsets, increases cytotoxic T cells in ascites, and alters gene expression in tumor cells and macrophages.
| S-EPMC11812249 | biostudies-literature
Project description:The cell line-derived xenografts and patient derived xenografts have limited use in cancer immunotherapy evaluation because an immune compromised host is required for xenotransplantation. Syngeneic mouse models are derived by transplanting established mouse cell lines or tumor tissues to strain matched mouse hosts, which are better suited to study the interplay between immune and tumor cells. We investigated the differences as well as similarities of a panel of ten mouse syngeneic models to features of human tumors by proteomics, which will provide valuable information to assist experimental biologists in model selection.
2019-12-03 | PXD011885 | Pride
Project description:The role of endothelial dysfunction in tubulointerstitial fibrosis associated with chronic kidney disease (CKD) is not well understood. In this study, we demonstrate that the activation of the endothelial tyrosine kinase TIE2 alleviates renal pathology in experimental CKD in mice. TIE2 activation was achieved using a human angiopoietin-2 (ANGPT2)-binding and TIE2-activating antibody (ABTAA), or through adult-induced endothelial-specific knockout of the vascular endothelial protein tyrosine phosphatase gene (Veptp). Both methods significantly protected CKD mice from endothelial dysfunction, peritubular capillary loss, tubular epithelial injury, and tubulointerstitial fibrosis. Conversely, silencing TIE2 through adult-induced endothelial-specific knockout of the Tie2 gene exacerbated CKD pathology. Additionally, we found that endothelial dysfunction promotes renal fibrosis not through endothelial-to-mesenchymal transition as previously expected, but by inducing the expression of pro-fibrotic PDGFB in tubular epithelial cells, a process that is inhibited by TIE2 activation. Our findings suggest that TIE2 activation via ABTAA warrants investigation in human CKD, where there is a significant unmet medical need.
2025-08-26 | GSE306281 | GEO
Project description:Comparison of transcriptional profiles of human umbilical vein endothelial cells (HUVECs) expressing wild-type vs. VM-causative mutant forms of TIE2/TEK. The effects of the most common Venous Malformation-causative mutations in the endothelial cell tyrosine kinase receptor: R849W and L914F, were tested. 743 genes were differentially expressed across the four groups. The 80 genes distinguishing between L914F and wild-type TIE2-expressing HUVECs were analyzed in greater detail. 3 batches each of: non-transfected, and wild-type TIE2, R849W-TIE2, and L914F-TIE2 overexpressing HUVECs were compared by exon-array profiling.
2013-06-04 | E-GEOD-46684 | biostudies-arrayexpress
Project description:Tumor cells that give rise to metastatic disease are a primary cause of cancer-related death and have not been fully elucidated in patients with lung cancer. Here, we addressed this question by using tissues from a mouse that develops metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. We identified a metastasis-prone population of tumor cells that differed from those with low metastatic capacity on the basis of having sphere-forming capacity in Matrigel cultures, increased expression of CD133 and Notch ligands, and relatively low tumorigenicity in syngeneic mice. Knockdown of jagged1 or pharmacologic inhibition of its downstream mediator phosphatidylinositol 3-kinase abrogated the metastatic but not the tumorigenic activity of these cells. We conclude from these studies on a mouse model of lung adenocarcinoma that CD133 and Notch ligands mark a population of metastasis-prone tumor cells and that the efficacy of Notch inhibitors in metastasis prevention should be explored. Keywords: two group comparison 344SQ subcutaneous tumors (from a lung adenocarcinoma cell line derived from a KrasLA1/+; p53R172HdelG/+ mouse that metastasizes widely following subcutaneous injection into syngeneic mice) were sorted by flow cytometry into CD133high and CD133low fractions. RNA samples from these fractions were processed and analyzed on Affymetrix Mouse Expression Array 430A 2.0 chips.
2011-02-24 | E-GEOD-15587 | biostudies-arrayexpress
Project description:Mouse syngeneic models serve as indispensable tools for elucidating tumor-immune interactions and assessing immunotherapy efficacy. In this study, we first conducted a comprehensive evaluation of six label-free protein quantification pipelines across 12 mouse syngeneic models, revealing that data-independent acquisition (DIA) significantly outperforms data-dependent acquisition (DDA) in terms of data coverage, reproducibility, and inter-model discrimination. We next performed an integrative multi-omics analysis to uncover molecular mechanisms associated with treatment response. Our analysis identified Dnmt3a and Igf2r, which are correlated with resistance to immune checkpoint inhibitors (ICIs), and highlighted key pathways including interferon signaling and oxidative phosphorylation that distinguish responders from non-responders. To facilitate broader research applications, we have developed an interactive web resource that shares our multi-omics datasets and analytical results, equipped with user-friendly tools for further exploration. It is freely accessible at https://muscreen.crownbio.com/syngeneic_omics. This resource aims to accelerate preclinical research and contribute to the development of personalized cancer therapies.
2025-07-28 | PXD064740 | Pride
Project description:Mouse syngeneic models serve as indispensable tools for elucidating tumor-immune interactions and assessing immunotherapy efficacy. In this study, we first conducted a comprehensive evaluation of six label-free protein quantification pipelines across 12 mouse syngeneic models, revealing that data-independent acquisition (DIA) significantly outperforms data-dependent acquisition (DDA) in terms of data coverage, reproducibility, and inter-model discrimination. We next performed an integrative multi-omics analysis to uncover molecular mechanisms associated with treatment response. Our analysis identified Dnmt3a and Igf2r, which are correlated with resistance to immune checkpoint inhibitors (ICIs), and highlighted key pathways including interferon signaling and oxidative phosphorylation that distinguish responders from non-responders. To facilitate broader research applications, we have developed an interactive web resource that shares our multi-omics datasets and analytical results, equipped with user-friendly tools for further exploration. It is freely accessible at https://muscreen.crownbio.com/syngeneic_omics. This resource aims to accelerate preclinical research and contribute to the development of personalized cancer therapies.
2025-07-28 | PXD064638 | Pride
Project description:To further characterize the role of endothelial Foxf2 in the maintenance of vascular function and examine a possible mediating effect of Tie2 signaling, we pharmacologically modulated Tie2 activity in mice and performed subsequent in vivo analyses together with studies on isolated brain vessels. Specifically, we applied AKB-9778, a selective small molecule inhibitor of vascular endothelial protein tyrosine phosphatase (Ptprb, VE-PTP) previously shown to stabilize the vasculature through Tie2 activation (Saharinen, et al., 2016; Shen et al., 2014). Mass-spectrometry analysis of isolated brain vessels from vehicle-treated Foxf2iECKO and Ctrl mice (Foxf2iECKO-Veh and Ctrl-Veh, respectively) confirmed the dysregulation of multiple proteins related to Tie2 signaling. Treatment with AKB-9778 for 48h restored their levels. Specifically, the abundance of Nos3, Nostrin and Gucy1b1 (implicated in nitric oxide metabolic process), Cldn5, Ctnnd1, Pecam1, and Rap1b (implicated in establishment of endothelial barrier), and Tie2, Flt1, and Itgb1 (implicated in angiogenesis) were all upregulated upon Tie2 activation. Collectively, these findings demonstrate that AKB-9778 rescues the deficiency of Tie2 signaling in mouse BECs lacking Foxf2.
2025-09-02 | PXD051839 | Pride
Project description:A time course of OTI CD8 T cells transferred to irradiated syngeneic hosts (or unirradiated hosts as control).
2007-11-02 | E-GEOD-1921 | biostudies-arrayexpress