Tumor Cell–Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression

Abstract

Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo. Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and Mena, an actin regulator, and involves increases in focal complex signaling and tumor-cell-mediated extracellular matrix (ECM) remodeling. Compared to Mena, higher levels of the pro-metastatic MenaINV isoform associate with α5, which enables 3D haptotaxis of tumor cells towards the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MenaINV and FN levels were correlated in two breast cancer cohorts, and high levels of MenaINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor-cell-intrinsic mechanism that promotes metastasis through ECM remodeling and ECM guided directional migration.

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

“…Some of the newer generation microfluidic devices incorporate pumps that provide a continuous flow of the soluble gradient and permit intermittent fluid analysis (Wu et al 2012), whereas others generate long-term stable gradients and have revealed that subtle differences in gradients can exert significant biological effects (Suraneni et al 2012). Stable ECM haptotactic gradients have also been developed using microfluidics and used to study 2D and 3D responses to multiple ECM cues such as FN, laminin, and vitronectin (Chan et al 2014;Oudin et al 2016a). Microfluidic channel width can also be used to directly modulate collagen alignment.…”

“…Intravital imaging studies in mice containing needles with EGF have shown that cells enter the needle by active migration only ). Since its inception this assay has been used to study both chemotactic and haptotactic responses (Oudin et al 2016a). More recently, a new microscale device was developed which incorporates multiple reservoirs in the delivery system to permit the time-resolved delivery of several compounds.…”

“…This new device permits the slow diffusion of drugs over time (Jonas et al 2015). These devices can be placed on the edges of tumors and, coupled with intravital imaging, can permit real-time imaging of the tumor cells response to large sustained local gradients in vivo (Oudin et al 2016a). Other implantable devices have been developed, such as the iNanivid (Williams et al 2016b), to visualize cell responses in vivo directly, and these approaches are likely to become far more powerful in the near future.…”

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

“…During the remodeling process, a tugging force is generated on the surrounding collagen fibers as they are bundled and arranged (Castella et al, 2010;Goffin et al, 2006;Murrell et al, 2015;Oudin et al, 2016). The presence of the myofibroblasts and the forces they generate have been linked to increased cancer cell invasion and motility (De Wever et al, 2008;Elkabets et al, 2011;Fuyuhiro et al, 2012).…”

Mathematical Modeling of Metastatic Cancer Migration through a Remodeling Extracellular Matrix

“…After perforating the basement membrane, the escaped cancer cells then must invade the ECM and travel through a meshwork of randomly oriented collagen fibers prior to intravasation into a blood vessel [8]. While maneuvering through the ECM, the direction and behavior of the migrating cells are greatly influenced by the physical and biomechanical properties of the ECM [9][10][11].…”