Autocrine Fibronectin Inhibits Breast Cancer Metastasis

Abstract

Both epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are linked to metastasis via their ability to increase invasiveness and enhance tumor-initiating capacity. Growth factors, cytokines, and chemotherapies present in the tumor microenvironment (TME) are capable of inducing EMT, but the role of the extracellular matrix (ECM) in this process remains poorly understood. Here, a novel tessellated three-dimensional (3D) polymer scaffolding is used to produce a fibrillar fibronectin matrix that induces an EMT-like event that includes phosphorylation of STAT3 and requires expression of β1 integrin. Consistent with these findings, analysis of the METABRIC dataset strongly links high-level fibronectin (FN) expression to decreased patient survival. In contrast, analysis of the MCF-10A progression series indicated that intracellular FN expression was associated with nonmetastatic cells. Therefore, differential bioluminescent imaging was used to track the metastasis of isogenic epithelial and mesenchymal cells within heterogeneous tumors. Interestingly, mesenchymal tumor cells do not produce a FN matrix and cannot complete the metastatic process, even when grown within a tumor containing epithelial cells. However, mesenchymal tumor cells form FN-containing cellular fibrils capable of supporting the growth and migration of metastatic-competent tumor cells. Importantly, depletion of FN allows mesenchymal tumor cells to regain epithelial characteristics and initiate tumor growth within a metastatic microenvironment. In contrast to the tumor-promoting functions of fibronectin within the ECM, these data suggest that autocrine fibronectin production inhibits the metastatic potential of mesenchymal tumor cells. .

Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche

“…Patients expressing high levels of both FN and TGM2 demonstrate decreased survival compared to those patients expressing low levels of these two genes (Fig. 2d) 9,19 . These data suggest that TG2 in conjunction with FN are clinically relevant markers of EMP whose enhanced expression within the primary tumor is consistent with metastatic disease progression.…”

“…In addition to these tumor cell autonomous effects of epithelial-mesenchymal plasticity (EMP) that take place at various steps in the metastatic process, differential EMP conversion rates within the primary tumor contribute to dynamic paracrine relationships between tumor cell populations of varying epithelial or mesenchymal status. We recently termed this concept, epithelial-mesenchymal heterogeneity (EMH) 8,9 . An understudied concept of EMP and EMH includes characterization of the epithelial phenotype that remerges after carcinoma cells transition to and from a mesenchymal state 10 .…”

Fibronectin in Cancer: Friend or Foe

“…Attention has particularly been paid to the fact that, with a few exceptions [101][102][103][104][105][106], the role of FN expression in tumor cells was primarily thought of as a tumor suppressor prior to the 1990s, yet later the consensus switched to its role being a metastatic promoter as aforementioned. It remains obscure why there are such two cut-off phases as to the different time periods for the obviously conflicting mainstream conceptions regarding the role of FN in tumor progression.…”

Undervalued ubiquitous proteins

“…Despite various proteins, such as integrins, even fibronectins help various cancer-triggering pathogenic stimuli to bind such as has been shown for various herpes viruses [112][113][114][115], hepatitis viruses [116][117][118], schistosomiasis [119][120][121][122][123], or opisthorchis [124,125], helicobacter [126][127][128][129], or mycoplasma [130][131][132][133][134]. Otherwise autocrine fibronectin inhibits cancer spread [135] and decreased fibronectin seems to be essential during metastasis [136] as natural killer cells (NK cells) mediated control can inhibit metastasis by increase of fibronectin [137].…”