Unknown,Transcriptomics,Genomics,Proteomics

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Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFbeta signaling pathways

ABSTRACT: Primary liver tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and a group of rare tumours exhibiting biliary and hepatocytic differentiation called combined hepatocholangiocarcinomas (cHCC-CC). To better define this latter group, we take advantage of a series of these tumours based on their morphological characteristics and we performed transcriptional analysis allowing thereafter global comparison with published data. We show that most cHCC-CCs express progenitor cell traits, are committed to biliary lineage and are mainly associated to the activation of Wnt/beta-catenin and TGFbeta signalling pathways. Wnt/beta-catenin pathway activation in cHCC-CC is evidenced by the expression of both its direct targets such as LEF1 and EPCAM. In addition, extracellular matrix (ECM) genes and ECM-remodelling genes which are upon the control of TGF profibrotic program were found up-regulated in cHCC-CC. Interestingly, we show that CC and most cHCC-CC share characteristics associated to a subtype of poorly differentiated HCC suggesting that these tumours could originate from a stem/progenitor cell. The plasticity of these cells may explain the phenotypical heterogeneity of these tumors with the maintenance of some hepatocellular differentiation features such as albumin expression. Interestingly, this is shared by at least one third of CC, raising the hypothesis of a potential continuum between CC, cHCC-CC and poorly differentiated HCC. Patients serie include 3 intra-hepatic CC, 7 typical HCC and 20 cHCC-CC that was used for microarray hybridisation. All these tumours did not show any mutation of the beta-catenin gene. The degree of hepatic fibrosis of the non-cancerous liver was graded according to the METAVIR classification. Paraffin sections were processed as described previously. Immunohistochemistry was done on standard slides for the series.

ORGANISM(S): Homo sapiens

SUBMITTER: Florent Dumont

PROVIDER: E-GEOD-35306 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.

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Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFbeta signaling pathways

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