Collagen-rich stroma in aggressive colon tumors induces mesenchymal gene expression and tumor cell invasion

Abstract

Gene expression-based classification systems have identified an aggressive colon cancer subtype with mesenchymal features, possibly reflecting epithelial-to-mesenchymal transition (EMT) of tumor cells. However, stromal fibroblasts contribute extensively to the mesenchymal phenotype of aggressive colon tumors, challenging the notion of tumor EMT. To separately study the neoplastic and stromal compartments of colon tumors, we have generated a stroma gene filter (SGF). Comparative analysis of stroma and stroma tumors shows that the neoplastic cells in stroma tumors express specific EMT drivers (ZEB2, TWIST1, TWIST2) and that 98% of differentially expressed genes are strongly correlated with them. Analysis of differential gene expression between mesenchymal and epithelial cancer cell lines revealed that hepatocyte nuclear factor 4α (HNF4α), a transcriptional activator of intestinal (epithelial) differentiation, and its target genes are highly expressed in epithelial cancer cell lines. However, mesenchymal-type cancer cell lines expressed only part of the mesenchymal genes expressed by tumor-derived neoplastic cells, suggesting that external cues were lacking. We found that collagen-I dominates the extracellular matrix in aggressive colon cancer. Mimicking the tumor microenvironment by replacing laminin-rich Matrigel with collagen-I was sufficient to induce tumor-specific mesenchymal gene expression, suppression of HNF4α and its target genes, and collective tumor cell invasion of patient-derived colon tumor organoids. The data connect collagen-rich stroma to mesenchymal gene expression in neoplastic cells and to collective tumor cell invasion. Targeting the tumor-collagen interface may therefore be explored as a novel strategy in the treatment of aggressive colon cancer.

Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome

“…1A), which has been associated with an increased VM ability [46]. On the other hand, on organotypic cultures rich in collagen I, which dominates the ECM of an advanced PDAC tumor [28], the CSC's VM was shifted to a typical epithelial-like phenotype with cells growing as a monolayer ( Fig. 2A) and expressing the highest levels of E-cadherin in 3D culture (Fig.…”

Molecular characterization of colorectal adenomas reveals POFUT1 as a candidate driver of tumor progression

“…Conversely, gene sets enriched in LRAs when compared to HRAs, like protein secretion, fatty-acid or heme metabolism, decreased in CRC, consistent with previous observations. 35 Nevertheless, by definition, stroma invasion is a process characteristic to cancer and not yet occurring in adenomas. Among upregulated genes/proteins in HRAs, genes of both epithelial and stromal origins were found.…”

Collagen Fibrils Mechanically Contribute to Tissue Contraction in an In Vitro Wound Healing Scenario

“…The quantification of traction forces via 2D TFM performed here provides only limited information about the forces that cells exhibit in their physiological environment. [43][44][45][46][47][48][49][50] Based on the finding that contraction and collagen fibril deposition are mechanically linked rather than successive processes, we speculate that an unbalanced collagen fibril-mediated tissue contraction might contribute to the development of pathological situations. Even under consideration of the above-mentioned limitations, the finding that scaffold contraction correlated linearly with collagen fiber density but not with single cell force strongly points toward collagen fibrils as an essential regulator and potential storage of cell traction forces during scaffold/tissue contraction.…”