Deciphering the molecular alterations sustaining an inverted apicobasal polarity phenotype in colorectal cancer clusters (Tumour Spheres with Inverted Polarity, TSIPs)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE152299 | GEO | 2021/01/31
REPOSITORIES: GEO
Similar Datasets
Project description:Deciphering the molecular alterations sustaining an inverted apicobasal polarity phenotype in colorectal cancer clusters (Tumour Spheres with Inverted Polarity, TSIPs)
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Project description:In proliferating neoplasms, microenvironment-derived selective pressures promote tumor heterogeneity by imparting diverse capacities for growth, differentiation and invasion. However, what makes a tumor cell respond to signaling cues differently from a normal cell is not well understood. In the Drosophila ovarian follicle cells, apicobasal-polarity loss induces heterogenous epithelial multilayering. When exacerbated by oncogenic-Notch expression, this multilayer displays an increased consistency in the occurrence of morphologically distinguishable cells adjacent to the polar follicle cells. Polar cells release the Jak-STAT ligand Unpaired (Upd), in response to which, neighboring polarity-deficient cells exhibit a precursor-like transcriptomic state. These cells activate the Snail-family transcription factor Escargot (Esg), among several regulons that we identify using single-cell transcriptomics. We also ascertain a similar relationship between Upd and Esg in normally-developing ovaries, where establishment of polarity determines early follicular differentiation. Overall, our results indicate that epithelial-cell polarity acts as a gatekeeper against microenvironmental selective pressures that drive heterogeneity.
2022-09-19 | GSE196885 | GEO
Project description:DNA replication errors are a major driver of evolutionâ??from single nucleotide polymorphisms to large-scale copy number variations (CNVs). Here we test a specific replication-based model to explain the generation of interstitial, inverted triplications. While no genetic information is lost, the novel inversion junctions and increased copy number of the included sequences create the potential for adaptive phenotypes. The modelâ??Origin-Dependent Inverted-Repeat Amplification (ODIRA)â??proposes that a replication error at pre-existing short, interrupted, inverted repeats in genomic sequences generates an extrachromosomal, inverted dimeric, autonomously replicating intermediate; subsequent genomic integration of the dimer yields this class of CNV without loss of distal chromosomal sequences. We used a combination of in vitro and in vivo approaches to test the feasibility of the proposed replication error and its downstream consequences on chromosome structure in the yeast Saccharomyces cerevisiae. We show that the proposed replication errorâ??the ligation of leading and lagging nascent strands to create a "closed" forkâ??can occur in vitro at short, interrupted inverted repeats. The removal of molecules with closed forks results in a hairpin-capped linear duplex that we show replicates in vivo to create an inverted, dimeric plasmid that subsequently integrates into the genome by homologous recombination, creating an inverted triplication. While other models have been proposed to explain inverted triplications and their derivatives, our model can also explain the generation of human, de novo, inverted amplicons that have a 2:1 mixture of sequences from both homologues of a single parentâ??a feature readily explained by a plasmid intermediate that arises from one homologue and integrates into the other homolog prior to meiosis. Our tests of key features of ODIRA lend support to this mechanism and suggest further avenues of enquiry to unravel the origins of interstitial, inverted CNVs pivotal in human health and evolution These are all CGH arrays comparing DNA copy number between evolved yeast strains and a euploid wt strain.
2015-10-30 | E-GEOD-74443 | biostudies-arrayexpress
Project description:Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted repeats are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a “hairpin” intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the hairpin. We also find evidence of short insertions and inversions at inverted duplication junctions, consistent with a DNA replication-based CNV mechanism. This process can give rise to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes High resolution array CGH; two-color experiment, clinical patient vs. normal control gDNA; sex mis-matched
2013-04-03 | E-GEOD-45395 | biostudies-arrayexpress
Project description:DNA replication errors are a major driver of evolution—from single nucleotide polymorphisms to large-scale copy number variations (CNVs). Here we test a specific replication-based model to explain the generation of interstitial, inverted triplications. While no genetic information is lost, the novel inversion junctions and increased copy number of the included sequences create the potential for adaptive phenotypes. The model—Origin-Dependent Inverted-Repeat Amplification (ODIRA)—proposes that a replication error at pre-existing short, interrupted, inverted repeats in genomic sequences generates an extrachromosomal, inverted dimeric, autonomously replicating intermediate; subsequent genomic integration of the dimer yields this class of CNV without loss of distal chromosomal sequences. We used a combination of in vitro and in vivo approaches to test the feasibility of the proposed replication error and its downstream consequences on chromosome structure in the yeast Saccharomyces cerevisiae. We show that the proposed replication error—the ligation of leading and lagging nascent strands to create “closed” forks—can occur in vitro at short, interrupted inverted repeats. The removal of molecules with two closed forks results in a hairpin-capped linear duplex that we show replicates in vivo to create an inverted, dimeric plasmid that subsequently integrates into the genome by homologous recombination, creating an inverted triplication. While other models have been proposed to explain inverted triplications and their derivatives, our model can also explain the generation of human, de novo, inverted amplicons that have a 2:1 mixture of sequences from both homologues of a single parent—a feature readily explained by a plasmid intermediate that arises from one homologue and integrates into the other homologue prior to meiosis. Our tests of key features of ODIRA lend support to this mechanism and suggest further avenues of enquiry to unravel the origins of interstitial, inverted CNVs pivotal in human health and evolution.
2015-10-30 | GSE74443 | GEO
Project description:Serrated adenocarcinomas are morphologically different from conventional adenocarcinomas. The serrated pathway has recently been proposed to represent a novel mechanism of colorectal cancer (CRC) formation. However, whether they are biologically different and truly form a distinct subclass of CRC, is not known. This study shows that the gene expression profile of serrated and conventional CRCs differs from each others and that serrated CRCs are not only morphologically novel, but also biologically distinct subclass of CRC. Keywords: molecular classification
2006-07-28 | GSE4045 | GEO
Project description:Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted repeats are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a “hairpin” intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the hairpin. We also find evidence of short insertions and inversions at inverted duplication junctions, consistent with a DNA replication-based CNV mechanism. This process can give rise to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes
2013-04-03 | GSE45395 | GEO
Project description:Although multiple determinants for establishing polarity in membranes of epithelial cells have been identified, the mechanism for maintaining the apicobasal polarity is not fully understood. Here, we show that the conserved Hippo kinase pathway plays a role in the maintenance of apicobasal polarity in the developing intestine of Caenorhabditis elegans. We screened suppressors of the mutation in wts-1, the gene encoding the LATS kinase homolog, whose deficiency leads to the disturbance of the apicobasal polarity of the intestinal cells and the eventual death of organisms. Multiple alleles of yap-1 and egl-44, each encoding the worm homologs of YAP/Yki and TEAD/Sd, respectively, were identified as suppressors. WTS-1 directly bound to YAP-1 and inhibited its nuclear accumulation in intestinal cells. We also found that NFM-1, the worm homolog of NF2/Merlin, functioned in the same genetic pathway as WTS-1 to regulate YAP-1 for maintaining cellular polarity. The transcriptome analysis using microarray identified several target candidates of the YAP-1-EGL-44 complex including TAT-2, encoding a putative P-type ATPase. In summary, we have delineated the conserved Hippo pathway in worms consisting of NFM-1-WTS-1-YAP-1-EGL-44 and prove that the proper regulation of YAP-1 by upstream NFM-1 and WTS-1 is esssential for the maintenance of apicobasal membrane identities of the growing intestine
2019-07-02 | GSE133667 | GEO
Project description:Scribble, a member of the LAP protein family, contributes to the apicobasal polarity (ABP) of epithelial cells. The LAP unique region (LUR) of these proteins is essential for ABP function, and includes a highly conserved Leucine Reach Repeat (LRR) domain. Here we study how the LRR domain of Scribble maintains ABP. We show that its concave surface participates in three types of mutually exclusive interactions 1. homodimerization serving as an auto-inhibitory mechanism, 2. interactions with a diverse set of polarity proteins, such as Llgl1, Llgl2, EPB41L2 and EPB41L5, which produce distinct multiprotein complexes, and 3. a direct interaction with the protein phosphatase, PP1, which forms a dimeric LRR domain-PP1 complex. Our results suggest that the latter complex maintains PP1 in the basolateral cell cortex in close proximity to PP1 targets. Such organization generates a dynamic network where PP1 could be immediately dispatched from the Scribble-PP1 complex to particular protein ligands. This mechanism for controlling dephosphorylation kinetics of phosphorylated proteins could be universal for all members of the LAP protein family, which includes Erbin, Lano, and the neuron-specific protein, Densin-180.
2021-11-03 | PXD028919 | Pride
Project description:Serrated adenocarcinomas are morphologically different from conventional adenocarcinomas. The serrated pathway has recently been proposed to represent a novel mechanism of colorectal cancer (CRC) formation. However, whether they are biologically different and truly form a distinct subclass of CRC, is not known. This study shows that the gene expression profile of serrated and conventional CRCs differs from each others and that serrated CRCs are not only morphologically novel, but also biologically distinct subclass of CRC. Experiment Overall Design: Total RNA was extracted from fresh frozen tumors with Trizol (GibcoBRL) and purified using RNeasy spin columns (Qiagen). The RNA quality was analyzed using a spectrophotometer and a Agilent 2100 Bioanalyzer (Agilent Technologies). Biotin labeled and fragmented cRNA was prepared from 8 micrograms of total RNA with procedures recommended for the HG-U133 GeneChip expression analysis (Affymetrix). The HG-U133A chips were hybridized, scanned and analyzed with Microarray Suite 5.0 software according to the manufacturerâ??s instructions (Affymetrix).
2007-10-27 | E-GEOD-4045 | biostudies-arrayexpress