ScRNAseq of orthotopic mismatch repair deficient (dMMR) or chromosomally instable (CIN) colorectal cancer
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ABSTRACT:
PROVIDER: PRJNA740039 | ENA |
REPOSITORIES: ENA
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Project description:Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) contain abundant CD8+ tumor infiltrating lymphocytes (TILs) responding to the abundant neoantigens from their unstable genomes. Priming of such tumor-targeted TILs first requires recruitment of CD8+ T cells into the tumors, implying that this is an essential prerequisite of successful dMMR anti-tumor immunity. We have discovered that selective recruitment and activation of systemic CD8+ T cells into dMMR CRCs strictly depends on overexpression of CCL5 and CXCL10 due to endogenous activation of cGAS/STING and IFN signaling by damaged DNA. TIL infiltration into orthotopic dMMR CRCs is neoantigen-independent and followed by induction of a resident memory-like phenotype key to the anti-tumor response. CCL5 and CXCL10 could be upregulated by common chemotherapies in all CRCs, indicating that facilitating CD8+ T cell recruitment underlies their efficacy. Induction of CCL5 and CXCL10 thus represents a tractable therapeutic strategy to induce TIL recruitment into CRCs where local priming can be maximized even in neoantigen-poor CRCs.
2021-07-19 | GSE178706 | GEO
Project description:In all primary cells analyzed to date, aneuploidy is associated with poor proliferation. Yet, how abnormal karyotypes affect cancer – a disease characterized by both aneuploidy and heightened proliferative capacity – is largely unknown. Here, I demonstrate that the transcriptional alterations caused by aneuploidy in primary cells are also present in chromosomally-unstable cancer cell lines, but are not common to all aneuploid cancers. Moreover, chromosomally-unstable cancer lines display increased glycolytic and TCA-cycle flux, as is also observed in primary aneuploid cells. The biological response to aneuploidy is associated with cellular stress and slow proliferation, and a 70-gene signature derived from primary aneuploid cells is a strong predictor of increased survival in several cancers. Inversely, a transcriptional signature derived from clonal aneuploidy in tumors correlates with high mitotic activity and poor prognosis. I speculate that there are two types of aneuploidy in cancer: clonal aneuploidy, which is selected during tumor evolution and is associated with robust growth, and sub-clonal aneuploidy, which is caused by chromosomal instability (CIN) and more closely resembles the stressed state of primary aneuploid cells. Nonetheless, CIN is not benign: a subset of genes upregulated in high-CIN cancers predict aggressive disease in human patients in a proliferation-independent manner. The mRNAs from 3 different mouse embryo fibroblast (MEF) lines that are chromosomally stable were compared with mRNAs from 3 different MEF lines that were chromosomally unstable due to mutations in either BUBR1 or CDC20
2013-10-01 | E-GEOD-49894 | biostudies-arrayexpress
Project description:In all primary cells analyzed to date, aneuploidy is associated with poor proliferation. Yet, how abnormal karyotypes affect cancer – a disease characterized by both aneuploidy and heightened proliferative capacity – is largely unknown. Here, I demonstrate that the transcriptional alterations caused by aneuploidy in primary cells are also present in chromosomally-unstable cancer cell lines, but are not common to all aneuploid cancers. Moreover, chromosomally-unstable cancer lines display increased glycolytic and TCA-cycle flux, as is also observed in primary aneuploid cells. The biological response to aneuploidy is associated with cellular stress and slow proliferation, and a 70-gene signature derived from primary aneuploid cells is a strong predictor of increased survival in several cancers. Inversely, a transcriptional signature derived from clonal aneuploidy in tumors correlates with high mitotic activity and poor prognosis. I speculate that there are two types of aneuploidy in cancer: clonal aneuploidy, which is selected during tumor evolution and is associated with robust growth, and sub-clonal aneuploidy, which is caused by chromosomal instability (CIN) and more closely resembles the stressed state of primary aneuploid cells. Nonetheless, CIN is not benign: a subset of genes upregulated in high-CIN cancers predict aggressive disease in human patients in a proliferation-independent manner.
2013-10-01 | GSE49894 | GEO
Project description:Samples were taken from colorectal cancers in surgically resected specimens in 35 colorectal cancer patients. The expression profiles were determined using Affymetrix Human Genome U133 Plus 2.0 arrays. Comparison between the sample groups allow to identify a set of discriminating genes that can be used for molecular markers for CIN phynotype. Specimens from 35 consecutive stage II and stage III patients who had undergone surgical resection of CRC were studied. Patients with familial adenomatous polyposis and HNPCC were excluded from the study. Specimens from tumors and corresponding normal tissues in surgically resected specimens were snap-frozen in liquid nitrogen and stored at -80 ºC until use. Parallel tumor specimens were formalin fixed and paraffin embedded for histological examination. DNA and RNA was extracted from paired tumor and normal tissue using frozen samples. The patients provided written, informed consent to the collection of specimens, and the local Ethics Committee approved the study protocol. MSI and LOH phenotype analysis were done as follows; Using DNA, we performed the polymerase chain reaction (PCR) and determined the MSI status. In addition to five microsatellite markers recommended by the National Cancer Institute workshop, we also used TP53, D18S46, D18S363 and D18S474.9 We determined LOH status in non–MSI-high tumors, because LOH is rare in MSI-high tumors and also interpretation of LOH is difficult in MSI-high tumors. We defined LOH at each locus as a 50% reduction in the height of one of two allele peaks in tumor DNA relative to non-neoplastic control DNA. LOH was defined as present if any of the markers on the same chromosome show LOH. In order to evaluate the severity of chromosomal instability based on the actual frequency of LOH among evaluable loci, we defined the LOH Ratio (%) as: LOH Ratio (%) = Total number of chromosomes with LOH / Total number of chromosomes that could be evaluated for LOH × 100. Depending on the LOH Ratio, we classified tumors as having high levels of chromosomal instability (CIN-high) (33% < LOH Ratio < 100%) or low levels of chromosomal instability (CIN-low) (0% < LOH Ratio <33%). Furthermore, CIN-high tumors were divided into two subgroups; CIN-high (mild type) (33% < LOH Ratio < 75%) and CIN-high (severe type) (75% < LOH Ratio <100%).
2012-07-03 | E-GEOD-30540 | biostudies-arrayexpress
Project description:Samples were taken from colorectal cancers in surgically resected specimens in 33 colorectal cancer patients. The expression profiles were determined using Affymetrix Human Genome U133 Plus 2.0 arrays. Comparison between the sample groups allow to identify a set of discriminating genes that can be used for molecular markers for CIN phynotype Specimens from 33 consecutive stage II and stage III patients who had undergone surgical resection of CRC were studied. Patients with familial adenomatous polyposis and HNPCC were excluded from the study. Specimens from tumors and corresponding normal tissues in surgically resected specimens were snap-frozen in liquid nitrogen and stored at -80degreesC until use. Parallel tumor specimens were formalin fixed and paraffin embedded for histological examination. DNA and RNA was extracted from paired tumor and normal tissue using frozen samples. The patients provided written, informed consent to the collection of specimens, and the local Ethics Committee approved the study protocol. MSI and LOH phenotype analysis were done as follows; Using DNA, we performed the polymerase chain reaction (PCR) and determined the MSI status. In addition to five microsatellite markers recommended by the National Cancer Institute workshop, we also used TP53, D18S46, D18S363 and D18S474.9 We determined LOH status in non–MSI-high tumors, because LOH is rare in MSI-high tumors and also interpretation of LOH is difficult in MSI-high tumors. We defined LOH at each locus as a 50% reduction in the height of one of two allele peaks in tumor DNA relative to non-neoplastic control DNA. LOH was defined as present if any of the markers on the same chromosome show LOH. In order to evaluate the severity of chromosomal instability based on the actual frequency of LOH among evaluable loci, we defined the LOH Ratio (%) as: LOH Ratio (%) = Total number of chromosomes with LOH / Total number of chromosomes that could be evaluated for LOH × 100. Depending on the LOH Ratio, we classified tumors as having high levels of chromosomal instability (CIN-high) (33% < LOH Ratio < 100%) or low levels of chromosomal instability (CIN-low) (0% < LOH Ratio <33%). Furthermore, CIN-high tumors were divided into two subgroups; CIN-high (mild type) (33% < LOH Ratio < 75%) and CIN-high (severe type) (75% < LOH Ratio <100%).
2012-11-29 | E-GEOD-34489 | biostudies-arrayexpress
Project description:Samples were taken from colorectal cancers in surgically resected specimens in 35 colorectal cancer patients. The expression profiles were determined using Affymetrix Human Genome U133 Plus 2.0 arrays. Comparison between the sample groups allow to identify a set of discriminating genes that can be used for molecular markers for CIN phynotype.
2012-07-04 | GSE30540 | GEO
Project description:Samples were taken from colorectal cancers in surgically resected specimens in 33 colorectal cancer patients. The expression profiles were determined using Affymetrix Human Genome U133 Plus 2.0 arrays. Comparison between the sample groups allow to identify a set of discriminating genes that can be used for molecular markers for CIN phynotype
2012-11-29 | GSE34489 | GEO
Project description:Tiled regions surrounding 5 human genes as 36mers, HBG2, TIMP3, SYN3, FLNA, FBX07. The first three of these genes, we tiled with various mismatch oligos in addition to 'perfect match' oligos. Keywords: Mismatch hybridization experiment Tiled perfect match and various designs of mismatch oligonucleotide for several human genes. Goal was to observe the influence of various MM types on hybridization behavior in human, and compare it to yeast (see related slide).
2010-05-05 | E-GEOD-13172 | biostudies-arrayexpress
Project description:Leaf development has been monitored chiefly by following anatomical markers. Analysis of transcriptome dynamics during leaf maturation revealed multiple expression patterns that rise or fall with age or that display age specific peaks. These were used to formulate a digital differentiation index (DDI), based on a set of selected markers with informative expression during leaf ontogeny. The leaf-based DDI reliably predicted the developmental state of leaf samples from diverse sources and was independent of mitotic cell division transcripts or propensity of the specific cell type. When calibrated by informative root markers, the same algorithm accurately diagnosed dissected root samples. We used the DDI to characterize plants with reduced activities of multiple CINCINNATA (CIN)-TCP growth regulators. These plants had giant curled leaves made up of small cells with abnormal shape, low DDI scores and low expression of mitosis markers, depicting the primary role of CIN-TCPs as promoters of differentiation. Delayed activity of several CIN-TCPs resulted in abnormally large but flat leaves with regular cells. The application of DDI has therefore portrayed the CIN-TCPs as heterochronic regulators that permit the development of a flexible and robust leaf form through an ordered and protracted maturation schedule.
2008-09-17 | GSE12691 | GEO
Project description:An irradiated but chromosomally stable CHO clone RT210B was used a reference to find differences in gene expression compared to radiation-induced chromosomally unstable isogenic clones. Equal quantities of two unstable different unstable clones were mixed prior to RNA extraction. Each mixture was tested twice versus the stable reference clone. Two different two clone mixtures were tested against the same chromosomally stable clone Keywords: repeat sample
2004-08-01 | GSE1626 | GEO