Fibronectin as a multiregulatory molecule crucial in tumor matrisome: from structural and functional features to clinical practice in oncology

Abstract

Deciphering extracellular matrix (ECM) composition and architecture may represent a novel approach to identify diagnostic and therapeutic targets in cancer. Among the ECM components, fibronectin and its fibrillary assembly represent the scaffold to build up the entire ECM structure, deeply affecting its features. Herein we focus on this extraordinary protein starting from its complex structure and defining its role in cancer as prognostic and theranostic marker.

Keywords: Actin cytoskeleton; Cancer; Cancer-associated fibroblasts; Dormant cells; Extracellular matrix; Extracellular vesicles; Fibrillogenesis; Fibronectin; Metastasis; Metastatic niche.

Fig. 1

Diagram of FN1 structure and its splice variants. a) FN1 monomer is composed by type I, type II and type III modules (FN I-III). The type III EDA (a) and EDB (b) repeats and the variable region V are alternatively spliced. The binding repeats for cellular surface integrin receptors and for other proteins, such as FN1, heparin, fibrin, collagen, fibrillin, tenascin, TGFβ, syndecan 4 and fibulin, are reported. The modules are grouped into functional domains: N-terminal 70-kDa domain (FNI1–9), the 120-kDa central binding domain (FNIII1–12) and the heparin-binding domain HEPII (FNIII12–14). The two cysteine residues at the C-terminus possess the thiol functional groups to build disulfide bonds with another FN1 monomer forming the FN1 dimeric protein. b) Schematic representation of FN1 alternative splicing variants. Created with BioRender.com

Fig. 2

FN1 fibrillogenesis process. a FN1 dimers have a compact conformation mediated by disulfide bonds at the C terminus of each subunit. b The FN1 binding to integrins induces conformational changes unfolding the protein, bring closer FN1 molecules at the cell surface and determines integrin clustering and activation with the recruitment of focal adhesion kinase (FAK), Src kinase, paxillin, and talin to generate focal complexes that activate polymerization of actin filaments. c The actin cytoskeletal network associates with the cytoplasmic domains of integrins forming a connection that is crucial for initial FN1 matrix generation. The RhoA GTPase-mediated cytoskeleton contractility and actin–myosin interactions induce cell traction, generating FN1 conformational alterations, thus opening cryptic FN1–FN1 binding sites, a requisite for FN1 fibrillogenesis. Created with BioRender.com

Fig. 3

FN1 as player in metastatic process and as diagnostic and therapeutic target. At the primary tumor site, the cancer cells and cancer associated fibroblasts (CAFs) deposit FN1. FN1 activates intracellular signaling, mediated by integrins, TLRs, Wnt/β catenin, and P13K, that lead to an increase of expression and secretion of FN1, MMPs, TGFβ. In parallel, FN1 is transferred by EVs. Cancer cells, with invasive capabilities, extravasate and reach a secondary organ, where tumor dormancy immune controlled may occur. Dormancy escape arises in the metastatic outgrowth in a permissive microenvironment with FN1 and collagen enriched ECM, affecting resistance to therapy. EDB isoform of FN1 is used as a biomarker for cancer diagnostic imaging and FN1 pathway as a target for therapeutic applications. Created with BioRender.com