Project description:To compare the expression profiles of colorectal cancers and liver metastatic lesion, 4 primary tumors and 3 liver metastases from CRC patients were subject to RNA-seq analysis
Project description:We carried out comprehensive analysis for the miRNA profiling of primary tumor and metastatic lesion which seems to be source of circulating miRNA. We picked up two patients who treated with primary tumor resection initially and received chemotherapy followed by surgical resection of liver metastasis. The total miRNA was isolated from frozen tissue specimens. SurePrint G3 Human miRNA microarray kit Rel.21.0 (Agilent Technologies) contains 2549 human microRNA probes. As previously reported, hsa-miR200c revealed specifically high expression in metastatic sites at both two cases. In two colorectal cancer patients, the frozen primary tumor, normal mucosa and liver-metastatic lesion were analyzed by microRNA microarray.
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.
Project description:We carried out comprehensive analysis for the miRNA profiling of primary tumor and metastatic lesion which seems to be source of circulating miRNA. We picked up two patients who treated with primary tumor resection initially and received chemotherapy followed by surgical resection of liver metastasis. The total miRNA was isolated from frozen tissue specimens. SurePrint G3 Human miRNA microarray kit Rel.21.0 (Agilent Technologies) contains 2549 human microRNA probes. As previously reported, hsa-miR200c revealed specifically high expression in metastatic sites at both two cases.
Project description:We present a novel approach for investigating transcriptomic differences between primary colorectal cancers (CRC) and distant CRC metastases, which may help to identify primaries at high risk for future dissemination and to inform the development of metastasis-targeted therapies. Eliminating tissue specificity of the “host” organs where tumors are located and adjusting for confounders such as exposure to chemotherapy and radiation, allows for an effective comparison of primary CRC and metastatic lesion transcriptomes at both the gene and pathway levels. Using this approach, our discovery-validation design identified that metastases are characterized by reduced epithelial-mesenchymal-transition (EMT) but increased MYC target and DNA repair pathway activities. The most significant gene-level expression differences between primaries and metastases were in FBN2 and MMP3, which showed over a 7-fold difference. In addition, we uncovered two distinct subtypes of CRC metastases that are characterized by either EMT-inflammatory or proliferative phenotypes, and demonstrated that none of the metastases examined were of consensus molecular subtype (CMS) 3 suggesting subtype exclusivity. Highlighting transcriptome differences between primary tumors and CRC metastases delineates pathways that may be activated in metastases and may assist in the development and/or selection of existing targeted treatment regimens for individuals with metastatic disease.
Project description:The phenomenon that metastatic lesion developed on injured sites has long been recognized in a number of cancers, such as melanoma. The factors associated with wound healing that attract circulating tumor cells have remained unknown, however. A patient with acral lentiginous melanoma presented with a metastatic lesion that appeared 1 month after trauma. To explore the molecular mechanism underlying the promotion of wound metastasis in melanoma, we performed microarray analysis of the metastatic lesions (n = 2) and the primary lesions (n = 3) of the patient. Using Human Genome U133 Plus 2.0 array, we compared global gene expression profiles of tissues derived from the patient’s primary (n = 3) and wound metastatic (n = 2) lesions to search for particular biological functions in genes of which expression intensities were increased in the wound metastasic lesions of melanoma.
Project description:The phenomenon that metastatic lesion developed on injured sites has long been recognized in a number of cancers, such as melanoma. The factors associated with wound healing that attract circulating tumor cells have remained unknown, however. A patient with acral lentiginous melanoma presented with a metastatic lesion that appeared 1 month after trauma. To explore the molecular mechanism underlying the promotion of wound metastasis in melanoma, we performed microarray analysis of the metastatic lesions (n = 2) and the primary lesions (n = 3) of the patient.
Project description:In this study, we comprehensively charted the cellular landscape of colorectal cancer (CRC) and well-matched liver metastatic CRC using single-cell and spatial transcriptome RNA sequencing. We generated 41892 CD45- non-immune cells and 196473 CD45+ immune cells from 27 samples of 6 CRC patients, and found that CD8_CXCL13 and CD4_CXCL13 subsets increased significantly in liver metastatic samples that exhibited high proliferation ability and tumor-activating characterization, contributing to better prognosis of patients. Distinct fibroblast profiles were observed in primary and liver metastatic tumors. The F3+ fibroblasts enriched in primary tumors contributed to worse overall survival by expressing pro-tumor factors. However, the MCAM+ fibroblasts enriched in liver metastatic tumors might promote generation of CD8_CXCL13 cells through Notch signaling. In summary, we extensively analyzed the transcriptional differences of cell atlas between primary and liver metastatic tumors of CRC by single-cell and spatial transcriptome RNA sequencing, providing different dimensions of the development of liver metastasis in CRC
Project description:Background: Liver metastasis is the major cause of death following a diagnosis of colorectal cancer (CRC) and is a major health burden. Most molecular studies of CRC have profiled primary tumor samples and not the metastasis samples. In this study, we compared the copy number profiles of matched primary and liver metastatic CRC to better understand how the genomic structure of primary CRC differs from the metastasis. This has important implications for whether it is justified to base therapeutic approaches solely on data from the primary tumour. Methods: Paired primary and metastatic tumours from 16 patients and their adjacent normal tissue samples were analyzed using Single-Nucleotide-Polymorphism (SNP) arrays to determine copy number alterations. Nine patients had a synchronous liver metastasis at the time of CRC diagnosis and 7 patients developed a liver metastasis metachronously. Genome-wide chromosomal copy number alterations were assessed, with particular attention to 189 genes known to be somatically altered in CRC and 25 genes that are clinically actionable in CRC. These data were analyzed with respect to the timing of primary and metastatic tissue resection and with exposure to chemotherapy. Results: The genomic divergence with the whole genome duplication correction applied the average percent copy number discordance across all pairs of samples was 22.02%. The pairs of tumour samples collected prior to treatment revealed a significantly higher copy number differences compared to previously treated liver metastasis samples (P=0.024). However, loss of heterozygosity (LOH) acquired in metastasis was significantly higher in previously treated liver metastasis samples compared to treatment naïve liver metastasis samples (P= 0.0064) and which included where KRAS mutation was present in the primary cancers but was not detectable in the metastatic sample following chemotherapy. With regard to 25 genes that are clinically actionable in CRC, amplification of the genes ERBB2, FGFR1, CDK8 or PIK3CA was observed in the metastatic tissue of 4 patients but not in the matched primary CRC. In these cases, knowledge of these metastatic specific alterations could have informed therapeutic decision making and may have improved patient outcome. Conclusion: Intra-patient genomic discrepancies observed between primary and metastatic tissue
Project description:FFPE primary CRC biopsies were harvested and run on the CRC DSA (Almac Diagnostics, UK). All primary tumours were pre-treatment and all patients developed progressive disease. Full patient response data to 5-FU/irinotecan treatment is measured in the advanced disease setting.