ECM deposition is driven by caveolin1-dependent regulation of exosomal biogenesis and cargo sorting

Abstract

ABSTRACT The composition and physical properties of the extracellular matrix (ECM) critically influence tumour cell behaviour, and ECM deposition and remodelling by stromal fibroblast populations is therefore pivotal for tumour progression. The molecular mechanisms by which stromal and tumour cell populations regulate ECM layering are poorly understood. Tumour-stroma interaction is critically dependent on cell-cell communication mediated by exosomes, small vesicles secreted by most cell types and generated within multivesicular bodies (MVBs). Here, we show that caveolin-1 (Cav1), an essential regulator of stromal remodelling and tumour cell fate, plays a central role in modulating both exosome biogenesis and exosomal protein cargo sorting through cholesterol-dependent mechanisms. Quantitative proteomics profiling revealed that a major share of Cav1-dependent exosomal cargoes are compsed of ECM proteins, one of the most important components being tenascin-C (TnC). Comparative functional assays demonstrated that Cav1 is required for fibroblast-derived exosomes to depose ECM and promote tumour cell invasiveness. Exosomes purified from Cav1WT cells, but not those from Cav1-null cells, were able to nucleate distant stromal niches in different organs in vivo . These findings suggest a key role for Cav1 as a cholesterol rheostat in MVBs, and seems to determine ECM deposition by eliciting ECM component sorting into specific exosome pools. These results, together with previous work, support a model in which Cav1 is a central regulatory hub for tumour-stroma interactions through a novel exosome-dependent ECM deposition mechanism.