Single-cell transcriptomics analysis of the tumor microenvironment from murine MC38 xenografts upon SHP099 treatment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE164908 | GEO | 2022/01/01
REPOSITORIES: GEO
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2012-02-07 | E-GEOD-35566 | biostudies-arrayexpress
Project description:We compared the expression of genes related to inflammatory cytotoxic functions between MSI and MSS (HLA class I negative and positive) gastrointestinal adenocarcinomas (GIACs), seeking evidence of differences in inflammatory mediators and cytotoxic T-cell responses. Twenty-two GIACs were divided into three study groups as a function of HLA class I expression and MSI phenotype. Comparison between eight high-level MSI (MSI-H) and 8 MSS/HLA+ (control) cancers identified 2170 differentially expressed genes (p< 0.05) after microarray analysis on the Affymetrix HG-U133-Plus-PM plate. We grouped genes in Gene Ontology functional categories: apoptotic programme (119 genes, p=5.1·10-7), leukocyte activation (32 genes, p=0.01), T cell activation (20 genes, p= 0.01), and cytokine production (19 genes, p= 0.04). Real-time RT-PCR and immunohistochemical evaluation were used to confirm some microarray data, finding that increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators were associated with greater infiltration by CD8+ T lymphocytes in the MSI-H group (p<0.001). Finally, tumours with immunohistochemical HLA class I negative pattern were not grouped together but rather in accordance with features of the gene expression profile of MSI or MSS tumours. As expected, genes associated with antigen processing machinery and MHC class I molecules (TAP2, B2m) were downregulated in MSS/HLA-ABC negative CRCs. In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour-host interactions and differentiate MSI from MSS cancers. The two types of tumours, MSI/HLA- and MSS/HLA-, showed marked differences in the composition and intensity of infiltrating leukocytes, suggesting that their immune escape strategies involve distinct pathways. Case-control study. Samples were selected according to immunological criteria: those with total loss of HLA antigens and those without alterations in the expression of HLA molecules. In addition, the microsatellite instability genotype of all the samples was also analyzed, resulting in microsatellite stability (MSS) and microsatellite instability (MSI) samples. Therefore, three groups of samples were selected: MSS/HLA+, MSS/HLA-, and MSI. The MSS/HLA+ group was used as the control.
2011-02-28 | E-GEOD-27544 | biostudies-arrayexpress
Project description:Background. Colorectal cancer develops through two main genetic instability pathways characterized by distinct pathologic features and clinical outcome. Results. We investigated colon cancer samples (23 characterized by microsatellite stability, MSS, and 16 by high microsatellite instability, MSI-H) for genome-wide expression of microRNA (miRNA) and mRNA. Based on combined miRNA and mRNA gene expression, a molecular signature consisting of twenty seven differentially expressed genes, inclusive of 8 miRNAs, could correctly distinguish MSI-H versus MSS colon cancer samples. Among the differentially expressed miRNAs, various members of the oncogenic miR-17-92 family were significantly up-regulated in MSS cancers. The majority of protein coding genes were also up-regulated in MSS cancers. Their functional classification revealed that they were most frequently associated with cell cycle, DNA replication, recombination, repair, gastrointestinal disease and immune response. Conclusions. This is the first report that indicates the existence of differences in miRNA expression between MSS versus MSI-H colorectal cancers. In addition, the work suggests that the combination of mRNA/miRNA expression signatures may represent a general approach for improving bio-molecular classification of human cancer.
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Project description:mRNA assays were performed on 51 samples of human colorectal tumors using Affymetrix HuGeneFL arrays containing 7129 probe-sets. We compared 38 microsatelite stable (MSS) tumors with 13 microsatellite instable-high (MSI) tumors to form a list of genes differing between the two types. In order to identify molecular signatures characterizing MSI tumors, we examined only MSI-high cancers and not MSI-low ones. Keywords: disease state analysis Human samples of 38 microsatellie stable and 13 microsatellite instable-high colorectal tumors, each from a separate patient, had mRNA assays performed using Affymetrix HuGeneFL arrays, with 7129 probe-sets. A supplementary Excel file (Colon_HuFL_logs.xls) is attached below that gives the log-transformed probe-set values. It also gives the p-values from T-tests comparing these values between MSS and MSI samples, as well as an estimated average fold-difference, for which the mathematical functions are explicitly given.
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Project description:Goal: Microsatellite-instable (MSI) tumors are one of the few cancers that respond to immune checkpoint blockade (ICB); however, the mechanism of MSI status development is unclear. Here, we report that protein phosphatase 2A (PP2A) deletion or inactivation converted cold microsatellite-stable (MSS) into MSI tumors. Objectives: Using RNA sequencing data of three CT26-shppp2r1a data and a CT26-scr data, we demonstrate that these intestinal tumors display differential core driver pathways.
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Project description:We designed a novel intratumoral (IT) IL-12 mRNA therapy to promote local IL-12 tumor production whilst mitigating systemic effects. A single IT dose of mouse (m)IL-12 mRNA induced IFNγ and CD8+ T cell-dependent tumor regression in multiple syngeneic mouse models including MC38-R, and animals with a complete response demonstrated immunity to re-challenge. In order to further investigate the impact of mIL-12 mRNA on the MC38-R TME, we performed tumor transcriptomic evaluation 24h and 7 days after a single IT dose of 0.5 micrograms IL-12 or control mRNA. mRNA was isolated from snap-frozen syngeneic tumors using an RNeasy mini kit (Qiagen) and quantified on the Affymetrix mouse 430 2.0 microarray.
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