Abstract
Epidermal Growth Factor Receptor (EGFR) is a known promoter of tumor progression and is overexpressed in lung cancers. Growth factor receptors (including EGFR) are known to interact with extracellular matrix (ECM) proteins, which regulate their activation and function. Fibulin-1 (FBLN1) is a major component of the ECM in lung tissue, and its levels are known to be downregulated in non-small cell lung cancers (NSCLC). To test the possible role FBLN1 isoforms could have in regulating EGFR signaling and function in lung cancer, we performed siRNA mediated knockdown of FBLN1C and FBLN1D in NSCLC Calu-1 cells. Their loss significantly increased basal (with serum) and EGF (Epidermal Growth Factor) mediated EGFR activation without affecting net EGFR levels. Overexpression of FBLN1C and FBLN1D also inhibits EGFR activation confirming their regulatory crosstalk. Loss of FBLN1C and FBLN1D promotes EGFR-dependent cell migration, inhibited upon Erlotinib treatment. Mechanistically, both FBLN1 isoforms interact with EGFR, their association not dependent on its activation. Notably, cell-derived matrix (CDM) enriched FBLN1 binds EGFR. Calu-1 cells plated on CDM derived from FBLN1C and FBLN1D knockdown cells show a significant increase in EGF mediated EGFR activation. This promotes cell adhesion and spreading with active EGFR enriched at membrane ruffles. Both adhesion and spreading on CDMs is significantly reduced by Erlotinib treatment. Together, these findings show FBLN1C/1D, as part of the ECM, can bind and regulate EGFR activation and function in NSCLC Calu-1 cells. They further highlight the role tumor ECM composition could have in influencing EGFR dependent lung cancers.
Highlights
Lung cancer is the leading cause of cancer related deaths worldwide
Non-small cell lung cancer (NSCLC) account for 85% of all lung cancers (Chen et al, 2014), with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) being the most common pathological NSCLC subtypes
With Epidermal growth factor receptor (EGFR) overexpression in lung cancers known to be correlated with poor prognosis (Chen et al, 2014), a significant increase in EGFR transcript levels was seen in the TCGA pan lung cancer (∼1.3 fold) and LUSC (∼1.7 fold) [datasets (Figure 1C)]
Summary
Lung cancer is the leading cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of the cases (Chen et al, 2014). Epidermal growth factor receptor (EGFR) is a protein that is expressed on the cell surface and influences cell growth, survival and motility (Normanno et al, 2006). The extracellular matrix (ECM), as a vital regulatory player in the tumor microenvironment provides structural support and regulates downstream signaling to control cell growth, survival, differentiation and motility (Lu et al, 2012; Pickup et al, 2014). A large number of matrix proteins are altered in lung cancers, the functional role of some of the major lung ECM proteins like Fibulin-1, Elastin, Nephronectin, Agrin, Laminin remain poorly documented (Burgstaller et al, 2017; Gocheva et al, 2017)
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