Force Matters: Biomechanical Regulation of Cell Invasion and Migration in Disease

Abstract

Atherosclerosis, cancer, and various chronic fibrotic conditions are characterized by an increase in the migratory behavior of resident cells and the enhanced invasion of assorted exogenous cells across a stiffened extracellular matrix (ECM). This stiffened scaffold aberrantly engages cellular mechanosignaling networks in cells, which promotes the assembly of invadosomes and lamellae for cell invasion and migration. Accordingly, deciphering the conserved molecular mechanisms whereby matrix stiffness fosters invadosome and lamella formation could identify therapeutic targets to treat fibrotic conditions, and reducing ECM stiffness could ameliorate disease progression.

Keywords: cancer; cardiovascular disease; extracellular matrix stiffness; fibrosis; invasion; migration.

Figure 1

Increased collagen deposition and thickening in breast cancer and cardiovascular disease promotes cell invasion and migration. (A) Second harmonics generation (SHG) imaging of human breast tumor biopsies containing normal adjacent tissue, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) showed that breast cancer transformation is accompanied by a progressive increase in interstitial collagen fibrils. Scale bar = 40 μm. Figure is modified, with permission, from [16]. (B) SHG imaging of healthy and atherosclerotic arteries showed atherosclerotic lesions have an increase in collagen fibrils. Scale bar = 75 μm. Figure is modified, with permission, from [20]. (C) LOX Inhibition using BAPN significantly reduced collagen thickening (color-coded fibrillar collagen diameter) and concurrently decreased the number of lung metastases in Polyoma middle-T-induced carcionomas lacking type II-TGF-beta (PyMT^mgko). Scale bar = 30 μm. Figure is modified, with permission, from [24]. (D) The number of inflammatory macrophages (anti-CD68; red) in aortic root lesions of atherosclerotic apoE-null mice was significantly decreased in the BAPN-treated mice. Scale bar = 200μm. Figure is modified, with permission, from [14].

Figure 2

Stiff substrates promote invadosome and lamella formation. (A) Breast carcinoma cells cultured on stiff gels formed a higher number of invadosomes and exhibited more proteolytic activity. Invadosomes are identified by colocalization of actin and cortactin and proteolytic activity of invadosomes can be visualized as the loss of fluorescently labelled fibronectin (Arrow: Invadopodia). Scale bar=10μm. Figure is modified, with permission, from [48]. (B) Nonmalignant mammary epithelial cells (MEC) cultured on stiff gels assembled larger focal adhesions (marker: vinculin) and had larger lamella (arrow). Figure is modified, with permission, from [31].

Figure 3

Key Figure. Biomechanical regulation of fibrotic disease across scales. ECM stiffening activates mechanotransduction signaling pathways that drive cell invasion and migration by promoting invadosome and lamella formation. Increased collagen crosslinking stiffens the ECM and drives integrin clustering, which subsequently results in focal adhesion kinase (FAK) activation and formation of FAK-Src complex. Stiff ECM can also promote PI3K signaling by potentiating signals transmitted from cell surface receptors, such as growth factor receptors. FAK-Src complex and PI3K can activate several pathways that lead to invadosome and lamella assembly via Rho GTPases. Activated Rac and Cdc42 GTPases can promote Arp2/3-nucleated dendritic actin network formation whereas RhoA GTPase activates formin-mediated linear F-actin assembly. Additionally, RhoA activates ROCK, which in turn enhances myosin contractibility to promote invadosome and lamella dynamics and reinforce integrin clustering. Currently available and pre-clinical drugs with potential utility in blocking mechanosignaling pathways are also listed (red font).