Cellular Traction Stresses Increase with Increasing Metastatic Potential

Abstract

Cancer cells exist in a mechanically and chemically heterogeneous microenvironment which undergoes dynamic changes throughout neoplastic progression. During metastasis, cells from a primary tumor acquire characteristics that enable them to escape from the primary tumor and migrate through the heterogeneous stromal environment to establish secondary tumors. Despite being linked to poor prognosis, there are no direct clinical tests available to diagnose the likelihood of metastasis. Moreover, the physical mechanisms employed by metastatic cancer cells to migrate are poorly understood. Because metastasis of most solid tumors requires cells to exert force to reorganize and navigate through dense stroma, we investigated differences in cellular force generation between metastatic and non-metastatic cells. Using traction force microscopy, we found that in human metastatic breast, prostate and lung cancer cell lines, traction stresses were significantly increased compared to non-metastatic counterparts. This trend was recapitulated in the isogenic MCF10AT series of breast cancer cells. Our data also indicate that increased matrix stiffness and collagen density promote increased traction forces, and that metastatic cells generate higher forces than non-metastatic cells across all matrix properties studied. Additionally, we found that cell spreading for these cell lines has a direct relationship with collagen density, but a biphasic relationship with substrate stiffness, indicating that cell area alone does not dictate the magnitude of traction stress generation. Together, these data suggest that cellular contractile force may play an important role in metastasis, and that the physical properties of the stromal environment may regulate cellular force generation. These findings are critical for understanding the physical mechanisms of metastasis and the role of the extracellular microenvironment in metastatic progression.

Metastatic ovarian cancer cell malignancy is increased on soft matrices through a mechanosensitive Rho/ROCK pathway

“…We found that, when cultured on soft matrices, OCCs exerted more force (Fig. 1Eb), a characteristic that is often indicative of increased metastatic phenotype (Kraning-Rush et al, 2012). Previous work has demonstrated that during invasion into the submesothelial environment, OCCs use myosin-dependent traction force to escape the mesothelial cell layer (Iwanicki et al, 2011).…”

Cancer cells become less deformable and more invasive with activation of β-adrenergic signaling

“…Myosin II binds to actin and regulates F-actin assembly and disassembly dynamics (Murrell et al, 2015), and also regulates intracellular tension (or pre-stress) and cell contractility, which can contribute to cell stiffness Murrell et al, 2015). Indeed, cancer cells that exhibit greater traction stresses show increased invasive behavior in vitro (Kraning-Rush et al, 2012;Volakis et al, 2014) and in vivo (Paszek et al, 2005;Volakis et al, 2014). Our results suggest that βAR signaling could enhance the contractility of cancer cells.…”

Src, p130Cas, and Mechanotransduction in Cancer Cells

“…p130Cas is therefore likely to maintain its mechanosensing capability in cancer cells and tissues while remaining in the wild-type form. This notion is supported by the findings that show that traction force generation, which is the primary consequence of mechanosensing, 84 positively correlates with the cells' metastatic potential, 106 where p130Cas also plays a role. 3 Taken together, p130Cas may facilitate downstream signaling in cancer cells when provided with enhanced mechanical cues such as matrix stiffening or increased cellgenerated traction forces (Fig.…”