A Study of the Gene Expression of Colorectal Liver Metastases: Tumour, ‘Halo’ and Liver Parenchyma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE38174 | GEO | 2020/05/01
REPOSITORIES: GEO
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Project description:Colorectal cancer is one of the most frequently occurring malignancies and a major cause of cancer death. Distant metastases in this disease most commonly develop in the liver and are often untreatable. Here, we show that citrullination of the extracellular matrix (ECM) by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases. Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is well recognized in rheumatoid arthritis, but largely undocumented in cancer. PAD4, a key enzyme responsible for catalyzing citrullination, is produced by metastatic colorectal cancer cells and found at higher levels in human liver metastases than in normal liver. Functional significance for citrullination in metastatic growth was evident in murine models where inhibition of citrullination, either globally by pharmacologic inhibition of PADs or specifically in colorectal cancer cells by PAD4 knockdown substantially reduced liver metastatic burden. Additionally, citrullination of a key ECM component collagen type I led to greater adhesion and decreased migration of colorectal cancer cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition (MET) and liver metastasis. Overall, our study revealed the potential for PAD4-dependant citrullination to drive the progression of liver metastasis. These data indicate that inhibition of citrullination could be exploited to prevent the development of liver metastases in colorectal cancer.
2018-10-18 | PXD010252 | Pride
Project description:The study identifies a set of genes through functional selection in an orthotopic colorectal cancer mouse model that play an important role in mediating colorectal cancer liver metastasis. We look at the gene profiling of metastatic colorectal cancer cells (L1 and L2) and non-mestastatic colorectal cancer cells (sw620 and sw480) using Affymetrix U133A oligonucleotide arrays.
2011-12-31 | GSE30687 | GEO
Project description:The study identifies a set of genes through functional selection in an orthotopic colorectal cancer mouse model that play an important role in mediating colorectal cancer liver metastasis. We look at the gene profiling of metastatic colorectal cancer cells (L1 and L2) and non-mestastatic colorectal cancer cells (sw620 and sw480) using Affymetrix U133A oligonucleotide arrays. 4 samples (each with triplicates) were analyzed. Genes with a fold-change ≥2 (P<0.05) were selected.
2011-12-31 | E-GEOD-30687 | biostudies-arrayexpress
Project description:Dissemination of primary tumors to distant anatomical sites has a substantial negative impact on patient prognosis. The liver is a common site for metastases from colorectal cancer, and patients with hepatic metastases have generally much shorter survival, raising a need to develop and implement novel strategies for targeting metastatic disease. The extracellular matrix (ECM) is a meshwork of highly crosslinked, insoluble, high molecular weight proteins maintaining tissue integrity and establishing cell-cell interactions. Emerging evidence identifies the importance of the ECM in cancer cell migration, invasion, intravasation, and metastasis. Here, we isolated the extracellular matrix from MC38 mouse liver metastases using our optimized method of mild detergent solubilization followed by biochemical enrichment. The matrices were subjected to label-free quantitative mass spectrometry analysis, revealing proteins highly abundant in the metastatic matrisome. The resulting list of differentially expressed proteins significantly predicted survival in patients with colorectal cancer but not other cancers with strong involvement of the extracellular matrix component. One of the proteins upregulated in liver metastatic ECM, Annexin A1, was not previously studied in the context of cancer-associated matrisome. Here we show that Annexin A1 was markedly upregulated in colon cancer cell lines compared to cancer cells of other origin, and also overrepresented in human primary colorectal lesions as well as hepatic metastases in comparison with their adjacent healthy tissue counterparts. In conclusion, our study provides a comprehensive ECM characterization of MC38 experimental liver metastases and proposes Annexin A1 as a putative target for this disease.
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Project description:We have developed Halo-seq, an RNA proximity labeling method that allows the quantification of subcellular transcriptomes. We have demonstrated the efficacy of Halo-seq here by using it to quantify chromatin-proximal, nucleolar, and cytoplasmic transcriptomes. In Halo-seq, RNA molecules in close proximity to a spatially restricted protein are specifically marked and biotinylated, facilitating their separation from bulk cellular RNA and their quantification.
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Project description:The goal was to identify genes that promote liver metastasis of colorectal cancer. Microarray analysis was performed to compare gene expression and altered biological pathways between a poorly metastatic CT26 cell line as compared to an isogenic highly metastatic CT26 FL3 cell line that was isolated by in vivo selection in an orthotopic mouse model of colon cancer metastasis to the liver.
2016-03-30 | GSE67675 | GEO
Project description:The goal was to identify genes that promote liver metastasis of colorectal cancer. Microarray analysis was performed to compare gene expression and altered biological pathways between a poorly metastatic CT26 cell line as compared to an isogenic highly metastatic CT26 FL3 cell line that was isolated by in vivo selection in an orthotopic mouse model of colon cancer metastasis to the liver. Gene expression in CT26-FL3 and parental CT26 cells were determined using the Agilent platform. Four independent samples each were analyzed.
2016-03-30 | E-GEOD-67675 | biostudies-arrayexpress
Project description:We performed whole exome sequencing and copy number analysis for 15 triplets, each comprising normal colorectal tissue, primary colorectal carcinoma, and its synchronous matched liver metastasis. We analyzed the similarities and differences between primary colorectal carcinoma and matched liver metastases in regards to somatic mutations and somatic copy number alterationss (SCNAs). The genomic profiling demonstrated mutations in APC(73%), KRAS (33%), ARID1A and PIK3CA (6.7%) genes between primary colorectal and metastatic liver tumors. TP53 mutation was observed in 47% of the primary samples and 67% in liver metastatic samples. The grouped pairs, in hierarchical clustering showed similar SCNA patterns, in contrast to the ungrouped pairs. Many mutations (including those of known key cancer driver genes) were shared in the grouped pairs. The ungrouped pairs exhibited distinct mutation patterns with no shared mutations in key driver genes. Four ungrouped liver metastasis samples had mutations in DNA mismatch repair genes along with hypermutations and a substantial number of copy number of alterations. Genomically, colorectal and metastatic liver tumors were very similar. However, in a subgroup of patients, there were genetic variations in liver metastases in the loss of DNA mismatch repair genes. Copy number analysis of Affymetrix CytoScanHD arrays was performed for 15 primary colorectal carcinoma and 15 samples of their matched liver metastases. 15 normal samples prepared from each of the patient was used as the reference for the study. Nexus Copy number 6.1 software was used for somatic copy number alteration analysis.
2014-03-01 | E-GEOD-53799 | biostudies-arrayexpress
Project description:Through an integrated transcriptome analysis of orthotopic colorectal cancer tumor-bearing mice and sham-operation mice, we showed the distinct immune microenvironment of pre-metastatic liver and identified MDSCs as the dominated cell type mediating pre-metastatic niche formation. MDSCs instead of other immune cell types were highly infiltrated in the pre-metastatic liver when compared with normal liver. Notably, immunosuppressive factors released by MDSCs such as HIF1α, iNOS, TGFβ were significantly up-regulated in the pre-metastatic liver. Increasing immune checkpoint molecules expression also reflected an immunosuppressive condition of pre-metastatic liver. The primary tumor may induce MDSCs accumulation via metabolic mechanism including glycolysis/gluconeogenesis, HIF-1 signaling pathway, and CCL28 chemokine axis. This study depicts the immune cell landscape of pre-metastatic cancer and primary CRC tumor, and provides insights into how MDSCs reshape the pre-metastatic niche facilitating circulating cancer cells colonization.
2020-04-30 | GSE147044 | GEO
Project description:We performed whole exome sequencing and copy number analysis for 15 triplets, each comprising normal colorectal tissue, primary colorectal carcinoma, and its synchronous matched liver metastasis. We analyzed the similarities and differences between primary colorectal carcinoma and matched liver metastases in regards to somatic mutations and somatic copy number alterationss (SCNAs). The genomic profiling demonstrated mutations in APC(73%), KRAS (33%), ARID1A and PIK3CA (6.7%) genes between primary colorectal and metastatic liver tumors. TP53 mutation was observed in 47% of the primary samples and 67% in liver metastatic samples. The grouped pairs, in hierarchical clustering showed similar SCNA patterns, in contrast to the ungrouped pairs. Many mutations (including those of known key cancer driver genes) were shared in the grouped pairs. The ungrouped pairs exhibited distinct mutation patterns with no shared mutations in key driver genes. Four ungrouped liver metastasis samples had mutations in DNA mismatch repair genes along with hypermutations and a substantial number of copy number of alterations. Genomically, colorectal and metastatic liver tumors were very similar. However, in a subgroup of patients, there were genetic variations in liver metastases in the loss of DNA mismatch repair genes.
2014-03-01 | GSE53799 | GEO