Abstract
Functional interplay between tumour cells and their neoplastic extracellular matrix plays a decisive role in malignant progression of carcinomas. Here we provide a comprehensive data set of the human HNSCC-associated fibroblast matrisome. Although much attention has been paid to the deposit of collagen, we identify oncofetal fibronectin (FN) as a major and obligate component of the matrix assembled by stromal fibroblasts from head and neck squamous cell carcinomas (HNSCC). FN overexpression in tumours from 435 patients corresponds to an independent unfavourable prognostic indicator. We show that migration of carcinoma collectives on fibrillar FN-rich matrices is achieved through αvβ6 and α9β1 engagement, rather than α5β1. Moreover, αvβ6-driven migration occurs independently of latent TGF-β activation and Smad-dependent signalling in tumour epithelial cells. These results provide insights into the adhesion-dependent events at the tumour–stroma interface that govern the collective mode of migration adopted by carcinoma cells to invade surrounding stroma in HNSCC.
Highlights
Functional interplay between tumour cells and their neoplastic extracellular matrix plays a decisive role in malignant progression of carcinomas
To study adhesive interactions between head and neck tumour cells and their extracellular matrix (ECM), we focused on fibroblasts, as they represent the major matrix-producing cells of the stroma, and exploited a pseudo-three-dimensional culture model in which carcinoma cells are plated on de-cellularized fibroblast matrices produced by carcinoma-associated fibroblasts (CAFs) or TIFs (Fig. 2a)
The first key message of our present work is that sustained expression of oncofetal FN in the stromal compartment of human head and neck squamous cell carcinomas (HNSCC) is strongly associated with decreased survival of patients
Summary
Functional interplay between tumour cells and their neoplastic extracellular matrix plays a decisive role in malignant progression of carcinomas. Avb6-driven migration occurs independently of latent TGF-b activation and Smad-dependent signalling in tumour epithelial cells These results provide insights into the adhesion-dependent events at the tumour–stroma interface that govern the collective mode of migration adopted by carcinoma cells to invade surrounding stroma in HNSCC. Tumour cell motile and invasive behaviours in three-dimensional environments have been extensively investigated ex vivo using gels composed of basement membrane proteins (Matrigel) or collagen I lattices from different sources with varying porosity and stiffness[16,17] These studies provide valuable insights into molecular circuitries that regulate cell migration, de-cellularized ECM produced by mature cultures of fibroblasts, albeit complex, more faithfully re-capitulates the composition and architecture of the desmoplastic stroma of human tumours[6]. We show that avb[6] integrin-stimulated migration occurs independently of direct TGF-b activation/signalling in tumour cells
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