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The transcriptional landscapes of a hepatoma cell line grown on scaffolds of Extracellular Matrix proteins

ABSTRACT: The in vivo microenvironment of cells is complex and highly dynamic, resulting from an interplay between matrix proteins with several other cues and biomolecules. Although the effects of the cellular niche have been investigated for a number of cell types using different molecular approaches, a comprehensive information on the global transcriptome at various stiffness levels of 3D scaffolds resulting derived from components of the extracellular matrix (ECM) are still lacking. In this study, we explored the effect of the biomechanical parameters of Collagen I and Matrigel (ECM) on transcriptional gene regulation in a cell culture system. Using Huh7 cells cultured on traditional cell culture plates or on the component of the ECM, we have generated transcriptome sequencing data that may be further explored to understand the differentiation and growth potential of this cell for the development of 3D cultures. Assessment of the hepatocyte phenotype in our data set would also be useful for the development of systems mimicking the in vivo structure and function of liver cells which still remains a challenge.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142206 | GEO | 2020/07/07

REPOSITORIES: GEO

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Project description:The liver is the most common site for colorectal cancer (CRC) metastasis and new tissue culture models are needed to study hepatic metastasis from CRC as none of the current models mimic the biological, biochemical and structural characteristics of the metastatic microenvironment. Decellularization provides a novel approach for the study of cancer extracellular matrix (ECM) as decellularized scaffolds retained their tissue-specific features and biological properties. In the present study we created a 3D model of CRC and matched CRC liver metastasis (CRLM) using patient-derived decellularized ECM scaffolds seeded with HT-29 CRC cell line. Here we show increased HT-29 cell proliferation and migration capability when cultured in cancer-derived scaffolds compared to same-patient healthy colon and liver tissues. CRLM scaffolds also induced activation of epithelial-mesenchymal transition (EMT) with cancer cells showing loss of E-cadherin expression and increased Vimentin expression. EMT was confirmed by gene expression profiling, with the most represented biological processes in CRLM-seeded scaffolds involving demethylation, deacethylation, cellular response to stress metabolic processes, response to oxygen level and to starvation. The complex 3D culture environment reduced the HT-29 cell response to anti-CRC drug 5-FU when used at standard IC50 determined in 2D cultures. In conclusion, our 3D culture system with patient-derived tissue-specific decellularized ECM better recapitulates the metastatic microenvironment compared to conventional 2D culture conditions and represents a relevant approach for the study of liver CRC metastasis formation and progression. Transcriptomic analysis was performed comparing the global gene expression profiles of HT29 cells grown on CRLM and HL scaffolds. The transcriptomic profile of each 3D subtype was compared with HT29 cells grown in plastic. Hierarchical clustering analysis revealed that the gene expression signature of recellularized CRLM scaffolds was more comparable to recellularized HL scaffolds, than to HT29 cells grown in 2D. Gene set enrichment analysis (GSEA) of the differently expressed genes (DEG) up-regulated in recellularized CRLM scaffolds compared to HT29 grown in 2D revealed that genes involved in demethylation, deacethylation and metabolic process belong to the most enriched biological pathways in repopulated-CRLM scaffolds. Comparing the DEG between recellularized CRLM scaffolds vs HT29 grown in 2D with a series of a-priori defined gene-set, called Hallmark, we obtained concordant results with the “HYPOXIA” and “EPITHELIAL_MESENCHYMAL_TRANSITION” pathway, enriched in recellularized CRLM, supporting the idea that 3D culture models are the ability to re-create a complex environment in terms of oxygen tension, nutrients, and metabolic gradient, similarly to the in vivo environment.

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The transcriptional landscapes of a hepatoma cell line grown on scaffolds of Extracellular Matrix proteins

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