Single-cell analysis for metastatic gastric adenocarcinoma
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ABSTRACT:
PROVIDER: EGAS00001004443 | EGA |
REPOSITORIES: EGA
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Project description:Peritoneal carcinomatosis (PC) occurs frequently in gastric adenocarcinoma (GAC) patients and confers poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC’s development/progression remain largely unknown. Here we characterized exome/transcriptome/immune landscapes of PC cells from 43 patients.
| EGAS00001003180 | EGA
Project description:Gastric cancer is one of the most aggressive cancers and is the second leading cause of cancer death worldwide. Approximately 40% of global gastric cancer cases occur in China, with peritoneal metastasis being the prevalent form of recurrence and metastasis in advanced disease (>50%). Currently, there are limited clinical approaches for predicting and treatment of peritoneal metastasis, resulting in a 6- month average survival time. By comprehensive genome analysis will uncover the pathogenesis of peritoneal metastasis. Here we describe a comprehensive whole-genome and transcriptome sequencing analysis of one advanced gastric cancer case, including non-cancerous mucosa, primary cancer and matched peritoneal metastatic cancer. The peripheral blood is used as normal control.
2019-06-12 | GSE64916 | GEO
Project description:Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 at lysine 22 (rpL40K22me3) by the lysine methyltransferase (KMT) SMYD5 regulates mRNA translation output to promote gastric adenocarcinoma (GAC) malignant progression with lethal peritoneal ascites. A biochemical-proteomic strategy identifies the mono-ubiquitin fusion protein partner rpL40 as the principal physiologic substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprograms protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in GAC patient samples and negatively correlate with clinical outcomes. SMYD5 ablation in vivo in familial and sporadic mouse models of malignant GAC blocks metastatic disease including peritoneal carcinomatosis (PC). Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to PI3K/mTOR inhibitors. Finally, combining SMYD5 depletion with PI3K/mTOR inhibition and CAR-T administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived PC. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates evolution of malignant GAC and nominates SMYD5 targeting as part of a potential cornerstone combination therapy to treat a deadly cancer.
2024-03-01 | GSE238257 | GEO
Project description:Purpose: Our study aimed to disclose the specific gene expression profile representing peritoneal relapses inherent in primary gastric cancers and to identify patients at high risk of peritoneal relapse in a prospective study on the basis of the molecular prediction. Experimental Design: RNA samples from 141 primary gastric cancer tissues after curative surgery were profiled using oligonucleotide microarrays covering 30,000 human probes. Firstly we constructed molecular prediction system and validated the robustness and prognostic validity of the analysis by 500 times multiple random sampling in 56 retrospective set consisting of 38 relapse free and 18 peritoneal relapse patients. Secondly we applied this prediction to 85 prospective set to assess the predictive accuracy and prognostic validity. Results: In retrospective phase, 500 times multiple random sampling analysis yielded 68% predictive accuracy in average and 22 gene expression profile associated with peritoneal relapse was identified. This prediction could identify significantly poor prognostic patients. In prospective phase, the molecular prediction yielded 76.9% overall accuracy. Kaplan–Meier analysis with peritoneal relapse free survival showed a significant difference between ‘good signature group’ and ‘poor signature group’ (Log-rank p=0.0017). Multivariate analysis by Cox regression hazards model revealed that the molecular prediction was the only independent peritoneal relapse prognostic factor. Conclusions: Gene expression profile inherent in primary gastric cancer tissues can be useful to predict peritoneal relapse prospectively after curative surgery and individualize postoperative management to improve the prognosis of advanced gastric cancers.
2009-03-04 | GSE15081 | GEO
Project description:Purpose: Our study aimed to disclose the specific gene expression profile representing peritoneal relapses inherent in primary gastric cancers and to identify patients at high risk of peritoneal relapse in a prospective study on the basis of the molecular prediction. Experimental Design: RNA samples from 141 primary gastric cancer tissues after curative surgery were profiled using oligonucleotide microarrays covering 30,000 human probes. Firstly we constructed molecular prediction system and validated the robustness and prognostic validity of the analysis by 500 times multiple random sampling in 56 retrospective set consisting of 38 relapse free and 18 peritoneal relapse patients. Secondly we applied this prediction to 85 prospective set to assess the predictive accuracy and prognostic validity. Results: In retrospective phase, 500 times multiple random sampling analysis yielded 68% predictive accuracy in average and 22 gene expression profile associated with peritoneal relapse was identified. This prediction could identify significantly poor prognostic patients. In prospective phase, the molecular prediction yielded 76.9% overall accuracy. KaplanâMeier analysis with peritoneal relapse free survival showed a significant difference between âgood signature groupâ and âpoor signature groupâ (Log-rank p=0.0017). Multivariate analysis by Cox regression hazards model revealed that the molecular prediction was the only independent peritoneal relapse prognostic factor. Conclusions: Gene expression profile inherent in primary gastric cancer tissues can be useful to predict peritoneal relapse prospectively after curative surgery and individualize postoperative management to improve the prognosis of advanced gastric cancers. Of 141 samples, 56 represented the retrospective phase and 85 represented the prospective phase.
2010-05-23 | E-GEOD-15081 | biostudies-arrayexpress
Project description:Peritoneal carcinomatosis is a frequent finding in patients with primary gastric cancer, and it is associated with a poor prognosis. A major mechanism in peritoneal carcinomatosis is the dissemination of cancer cells into the abdominal cavity, mainly in diffuse gastric adenocarcinoma. The features that enable diffuse primary gastric tumours to develop peritoneal dissemination have been little investigated and are only incompletely understood. We therefore compared the gene expression profile in patients with diffuse primary gastric cancer with and without peritoneal carcinomatosis. Specimens from consecutive gastric cancer patients with and without peritoneal carcinomatosis were investigated using oligonucleotide microarrays. Keywords: Disease state analysis
2008-01-31 | GSE8657 | GEO
Project description:Peritoneal carcinomatosis (PC) originating from colorectal cancer (CRC) is associated with a poor prognosis and rapid disease progression. Metastasis is the major cause of death in patients with CRC whereas primary locoregionally circumscribed tumors are mostly curable. Due to the lack of appropriate and realistic mouse models for metastasis of CRC until recently, the research about metastasis of these tumors and possible therapeutic options is still in its infancy. With the establishment of murine CRC tumor organoids, mouse models were established which realistically mimic the process of tumor cell metastasis to the liver and the lung. However, to date no appropriate model for PC is described. Here, we establish a realistic model for peritoneal metastasis of colorectal cancer upon surgical transplantation of tumor organoids into the cecum wall. This mouse model for PC recapitulates human PC which makes it an ideal model for research of the biology of metastasis of colorectal cancer to the peritoneal cavity and for its usage for preclinical drug screening as well as for the evaluation of new therapeutic approaches which are highly needed in clinical reality.
2022-06-27 | GSE202454 | GEO
Project description:How epigenetic deregulation affects gene expression patterns in subclones of the same tumor is poorly known. Peritoneal Carcinomatosis (PC) is a condition in which multiple metastases of the same abdominal tumor develop in the peritoneal cavity and intra-peritoneal organs, thus defining different ecosystems of the same cancer. PITCHER addresses the variations in epigenetically regulated gene expression between different subclones of PC in relation with cell mechanoresponses, providing insights on how cancer epigenetic landscapes evolve under environmental pressures and on strategies used by cancer cells to adapt to the transition from one ecosystem to the other.
PITCHER is a network of 10 teams from Lyon, Grenoble and Marseille, based on data and specimen collection of patients who have undergone a surgery for a peritoneal carcinomatosis of ovarian or colorectal origin. PC lesions and eventually matched specimens of primary tumors will be collected in the same patients at the time of the surgery or eventually retrieved from already existing samples. Epigenetic landscapes will be analyzed by a bioinformatics pipeline combining exome sequencing, transcriptome and methylome to identify "epigenetic hotspots", and their variations across lesions will be evaluated. These analyses will be realized in fresh (when available) or pre-existing samples. When possible, organoid cultures and animal models will be derived from multicellular structures in peritoneal fluids and membrane, cytoskeletal and nucleoskeletal mechanoresponses will be characterized using Atomic Force Microscopy. The role of tumor axonogenesis, a process of neo-formation of axon fibers in tumors, will be addressed. Experimental studies of cell responses to therapy will be performed to derive mathematical predictive models. All components will be integrated in a systems biology map of PC.
| 2364325 | ecrin-mdr-crc
Project description:Characterizations of ascites proteome from ovarian peritoneal carcinomatosis (PC) and gastric PC have demonstrated that ascites contains elevated pro-tumorigenic factors. Reasoning that the composition of ascitic fluid might offer insight into the memory of key biological events occurring intra-abdominally, we hypothesized that paracrine factors essential for survival and growth of peritoneal deposits are secreted into and circulate within ascitic fluid. Our data from cytokine array profile suggest that ascites contains biologically active ligands capable of supporting cellular functions of cancer cells. To decipher downstream signalling pathways activated in cancer cells when exposed to ascites, we performed gene expression analysis of Colo-205 cells upon exposure to PC ascites and ligand inhibitor.
2022-02-22 | GSE189137 | GEO
Project description:Intra-individual tumoral heterogeneity (ITH) is a hallmark of solid tumors and impedes accurate genomic diagnosis and selection of proper therapy. The purpose of this study was to identify ITH of ovarian serous adenocarcinomas (OSAs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling, and DNA methylation profiling of four OSA genomes using multiregional biopsies from 13 intraovarian lesions, 12 extraovarian tumor lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSAs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, 8 shared, and 24 private mutations were observed in known cancer-related genes,. but common mutations had a higher mutant allele frequency and included TP53 mutations in all four OSAs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA, and RB1 were also identified. Of note, the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a polyseeding origin of somatic mutations in ascitic cells. Our results demonstrate that despite ITH, somatic mutations, CNAs, and DNA methylations in both â??commonâ?? category and cancer-related genes were highly conserved in ascitic cells of OSAs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumor cells may serve as a potential resource to discover somatic mutations of primary OSA with diagnostic and therapeutic relevance. Genome wide DNA methylation profiling of ascitic cells as well as biopsies from ovarian serous adenocarcinomas cases obtained by Illumina Infinium 450k Human DNA methylation Beadchip Bisulphite converted DNA from the 16 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip
2016-08-09 | E-GEOD-85293 | biostudies-arrayexpress