Abstract: Colonic cancers with a serrated morphology have been proposed to comprise a molecularly distinct tumor entity following an alternative pathway of genetic alterations independently of APC mutations. Here we demonstrate that intestinal cell specific expression of oncogenic K-rasG12D in mice induces serrated hyperplasia, which is characterized by p16ink4a overexpression and induction of senescence. Deletion of Ink4a/Arf in K-rasG12D expressing mice prevents senescence and leads to invasive, metastasizing carcinomas with morphological and molecular alterations comparable to human KRAS mutated serrated tumors. Thus, we suggest that oncogenic K-ras is sufficient to initiate an alternative, serrated pathway to colorectal cancer and hence propose RAS-RAF-MEK signaling apart from APC as an additional gatekeeper in colorectal tumor development.
Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis.
Specimen part
View SamplesGene expression studies are used to help identify disease-associated genes, by comparing the levels of expressed transcripts between cases and controls, and to identify functional genetic variants known as expression quantitative loci (eQTLs). While many of these studies are performed in blood or lymphoblastoid cell lines due to tissue accessibility, the relevance of expression differences in tissues that are not the primary site of disease is unclear. Further, many eQTLs are tissue specific. Thus, there is a clear and compelling need to conduct gene expression studies in tissues that are specifically relevant to the disease of interest. One major technical concern about using autopsy-derived tissue is how representative it is of physiologic conditions, given the effect of postmortem interval on tissue degradation.
Postmortem cardiac tissue maintains gene expression profile even after late harvesting.
Specimen part, Disease, Cell line
View SamplesComparison of the changes in mitochondrial gene expression of cells in which extracellular growth factors and/or mitogens have been added.
Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis.
Specimen part
View SamplesDepending on the tumor type IB kinase (IKK) can act as tumor promoter or tumor suppressor in various malignancies. Here we demonstrate a key function of IKK in the suppression of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKK kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of IFN expressing M1-like myeloid cells. In IKK mutant mice M1-like polarization is not controlled in a cell autonomous manner but depends rather on the interplay of both IKK mutant tumor epithelia and immune cells.
IKKα promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells.
Specimen part, Time
View SamplesSeveral aspects common to a Western lifestyle, including obesity and decreased physical activity, are known risks for gastrointestinal cancers. There is an increasing amount of evidence suggesting that diet profoundly affects the composition of the intestinal microbiota. Moreover, there is now unequivocal evidence linking a dysbiotic gut to cancer development. Yet, the mechanisms through which high-fat diet (HFD)-mediated changes in the microbial community impact the severity of tumorigenesis in the gut, remain to be determined.
High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity.
Sex, Age, Specimen part, Treatment
View SamplesThis scRNA-seq experiment is an integral part of a manuscript with the above title. Our analysis of the scRNA-seq data suggests that activated CARD11 promotes immunoglobulin class-switching in germinal center B cells and generation of IgG1-secreting plasma cells. Overall design: Single-cell suspensions were prepared from spleens harvested from mice 5 days post immunization with sheep red blood cells. B cells were enriched using an immunomagnetic negative selection kit. scRNA-seq was performed using the Chromium product suite by 10x Genomics.
Activated CARD11 accelerates germinal center kinetics, promoting mTORC1 and terminal differentiation.
Cell line, Subject
View SamplesIn order to examine the consequences of human miR-34a induction on the transcriptome, HCT116 cells (a colon cancer cell line) were infected with a retrovirus that produces miR-34a. Gene expression profiles were then monitored using Affymetrix microarrays.
Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.
No sample metadata fields
View SamplesmRNA profiles of thousands of human tumors are available, but methods to deduce oncogenic signaling networks from these data lag behind. It is especially challenging to identify main-regulatory routes, and to generalize conclusions obtained from experimental models. We designed the bioinformatic platform R2 in parallel with a wet-lab approach of neuroblastoma. Here we demonstrate how R2 facilitates an integrated analysis of our neuroblastoma data. Analysis of the MYCN pathway suggested important regulatory connections to the polyamine synthesis route, the Notch pathway and the BMP/TGF pathway. A network of genes emerged connecting major oncogenes in neuroblastoma. Genes in the network carried strong prognostic values and were essential for tumor cell survival.
Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
DOCK8 is critical for the survival and function of NKT cells.
Sex, Specimen part
View SamplesAnalysis of DOCK8 deficient animals revealed a novel marker of NKT cell development, the integrin CD103. The role of CD103 was further investigated by RNA microarray comparing CD103 negative versus positive NKT cells.
DOCK8 is critical for the survival and function of NKT cells.
Sex, Specimen part
View Samples