Spatial transcriptomics data of GAN-KP tumor treated with regorafenib
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE214363 | GEO | 2022/10/05
REPOSITORIES: GEO
Similar Datasets
Project description:Developing effective model systems to evaluate new potential chemotherapeutic reagents is critical. Three-dimensional cell cultures, such as spheroids, aid in bridging the gap between commonly used monolayer cell cultures and significantly more complex and expensive animal models. Spheroid model systems contain pathophysiological and chemical gradients similar to an in vivo tumor, which ultimately form distinct cellular subpopulations. In the spatial SILAC model, labels are pulsed into the spheroid at discrete time windows during development. These media pulses result in labeled proteins in distinct regions of the spheroid, which allows for tracing of quantitative proteomic changes to be correlated to different cellular subregions. In this study, we use the Spatial SILAC model to evaluate the proteomic response of a colon carcinoma spheroid to the multikinase inhibitor Regorafenib. We determined regorafenib to be an effective kinase inhibitor which significantly altered whole spheroid proliferation and resulted in increased apoptosis when the signal was averaged for all cells in the culture. However, when regorafenib treatment is more closely examined among the cellular subpopulations, drastic differences are observed for how the drug impacted the proteome of the necrotic spheroid core and the proliferating outer regions. Whole spheroid and outer region analysis shows that regorafenib treatment inhibited critical pathways such as mTOR signaling, ERK/MAPK signaling, and colorectal cancer metastasis signaling. However, analysis of the core shows that regorafenib had an entirely different effect, including upregulation of MAPK1 and KRAS, possibly indicating drug resistance within these late apoptotic cells. Ultimately, these combinatory studies can be used to further understanding of drug metabolism is different cellular subpopulations and provide valuable information to ultimately improve the accuracy of therapeutic testing.
2024-08-09 | PXD038958 | Pride
Project description:Spatial transcriptomics data of GAN-KP tumor treated with regorafenib
| PRJNA885067 | ENA
Project description:We have now developed an organoid-based model of gastric cancer from GAstric Neoplasia (GAN) mice, which express Wnt1 and the enzymes COX2 and microsomal prostaglandin E synthase 1 in the stomach. Both p53 knockout (GAN-p53KO) organoids and KRASG12V-expressing GAN-p53KO (GAN-KP) organoids were generated by genetic manipulation of GAN mouse–derived tumor (GAN-WT) organoids. To uncover the molecular mechanism underlying the intratumoral heterogeneity of GAN-KP tumors, we performed spatial transcriptomics analysis with the 10× Genomics Visium platform, which allows characterization of the spatial topography of gene expression.
2021-10-21 | GSE186290 | GEO
Project description:To develop a syngeneic mouse model of metastatic gastric cancer, we established the tumor organoids from gastric tumor arising in GAstric Neoplasia (GAN) mice (GAN-WT) which express Wnt1 and the PGE2 synthesis enzymes COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in the stomach epithelium. Furthemore, GAN-WT organoids were genetically manupilated into p53 knockout organoids (GAN-p53KO) and KrasG12V-expressing GAN-p53KO organoids (GAN-KP).
2021-06-15 | GSE178087 | GEO
Project description:We report the RNA sequencing data from the REPEAT study, in which patients with beyond first-line esophagogastric cancer were treated with regorafenib and paclitaxel. For the RNA sequencing, biopsies from metastatic lesions were obtained on baseline (n=21) and fifteen days following treatment initiation (n=13). PURPOSE: Regorafenib monotherapy, a multikinase-inhibitor of angiogenesis, tumor microenvironment, and oncogenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in advanced esophagogastric cancer (EGC) patients refractory to first-line treatment, and explore potential biomarkers. METHODS: Patients received paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on day 1-21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall- (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second/third line systemic treatment. Paclitaxel pharmacokinetics were assessed using D1 and D15 samples. We performed ELISA measurements of galectin-1, RNA sequencing and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses. RESULTS: In the dose-escalation cohort (n=14), the MTD of regorafenib was 120 mg. Thirty-four patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade ≥3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up 7.8 months). OS (p=0.08) and PFS (p=0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p<0.05); no associations were observed with toxicity or efficacy. An increase in circulating galectin-1 compared to baseline was associated with shorter OS (p<0.01). Enrichment of angiogenesis-related gene expression was observed in short-survivors measured by RNA sequencing. Chromosome 19q13.12-q13.2 amplification was associated with shorter OS (p=0.02) and PFS (p=0.02). CONCLUSION: Treatment with regorafenib and paclitaxel is tolerable and shows promising efficacy in advanced EGC refractory to first-line treatment. Galectin-1 and chromosome 19q13.12-q13.2 amplification could serve as negative predictive biomarkers for treatment response.
2022-03-11 | GSE198136 | GEO
Project description:Low-dose regorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR antibody) but produced higher T cell activation and M1 macrophage polarization, Regorafenib increased M1/M2 ratio of BMDMs polarization and proliferation/activation of co-cultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream CREB-KLF4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells, whereas macrophage deletion negated regorafenib’s antitumor effects. Synergistic antitumor efficacy between low-dose regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.
2021-01-27 | GSE148947 | GEO
Project description:Melanoma is a malignant tumor with a terrible prognosis. In this study, we showed regorafenib has the ability to limit the growth, invasion and metastasis of melanoma cells but to upregulate apoptosis-prompting markers (cleaved-PARP and Bax). Moreover, ERK/E2F3 signaling influences regorafenib's ability to suppress melanoma cell growth. Ultimately, regorafenib significantly inhibits tumor growth in a dose-dependent manner in vivo.
2024-09-06 | GSE273844 | GEO
Project description:Regorafenib increased M1/M2 ratio of BMDMs polarization and proliferation/activation of co-cultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream CREB-KLF4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells, whereas macrophage deletion negated regorafenib’s antitumor effects. Synergistic antitumor efficacy between low-dose regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.
2021-01-27 | GSE148948 | GEO
Project description:Spatial transcriptome analysis of gastric cancer which GAN-KP transplanted C57BL/6J mouse
| PRJNA773137 | ENA
Project description:We demonstrate that regorafenib treatment suppresses multiple canonical pathways and transcriptions factors We used microarrays to analyze the potential mechanism by which regorafenib regulates gene expression.
2022-04-28 | GSE149131 | GEO