Differential Matrix Rigidity Response in Breast Cancer Cell Lines Correlates with the Tissue Tropism

Abstract

Metastasis to a variety of distant organs, such as lung, brain, bone, and liver, is a leading cause of mortality in the breast cancer patients. The tissue tropism of breast cancer metastasis has been recognized and studied extensively, but the cellular processes underlying this phenomenon, remain elusive. Modern technologies have enabled the discovery of a number of the genetic factors determining tissue tropism of malignant cells. However, the effect of these genetic differences on the cell motility and invasiveness is poorly understood. Here, we report that cellular responses to the mechanical rigidity of the extracellular matrix correlate with the rigidity of the target tissue. We tested a series of single cell populations isolated from MDA-MB-231 breast cancer cell line in a variety of assays where the extracellular matrix rigidity was varied to mimic the environment that these cells might encounter in vivo. There was increased proliferation and migration through the matrices of rigidities corresponding to the native rigidities of the organs where metastasis was observed. We were able to abolish the differential matrix rigidity response by knocking down Fyn kinase, which was previously identified as a critical component of the FN rigidity response pathway in healthy cells. This result suggests possible molecular mechanisms of the rigidity response in the malignant cells, indicating potential candidates for therapeutic interventions.

Synthetic Materials in the Study of Cell Response to Substrate Rigidity

“…24,47,73,75 In general, the transformed cells appeared to be relatively insensitive to substrate rigidity when compared with untransformed fibroblasts. 75 Paszek et al 54 and Kostic et al 40 found similar changes in rigidity response in transformed mammary epithelial cells. Normal mammary epithelial cells showed increased spreading, 40,54 proliferation, 40 FAK pY397 phosphorylation 54 and recruitment of vinculin to adhesion sites 54 with increased substrate rigidity.…”

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

“…Much of the early focus has been on the obvious changes in stiffness, since the stroma surrounding most tumors often becomes more rigid and dense due to an enrichment of collagen type I and fibronectin (Miles and Sikes, 2014;Pickup et al, 2014). This increase in rigidity leads to an increase in tumor cell proliferation, migration and invasion (Alexander et al, 2008;Charras and Sahai, 2014;Jerrell and Parekh, 2014;Kostic et al, 2009;Parekh and Weaver, 2009;Tilghman et al, 2010;Ulrich et al, 2009;Umesh et al, 2014).…”

“…A variety of mechanical forces are present in the tumor environment; however, much effort has focused solely on the increased rigidity of the stroma (Kostic et al, 2009;Levental et al, 2009;Paszek et al, 2005). In this study, we utilize an in vitro mechano-invasion assay (Menon and Beningo, 2011) to test the impact of a different form of mechanical stimuli on the ability of the cell to invade (Fig.…”

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

“…For instance, pioneering studies by Weaver and colleagues have demonstrated that increased matrix stiffness can induce a malignant phenotype in mammary epithelial cells by leading to increases in both Rho activation and actomyosin contractility (Paszek et al, 2005), with further studies directly implicating contractility in increasing matrix stiffness and cancer progression (Samuel et al, 2011). Although most of these studies linked increased matrix stiffness to tumor progression, breast cancer metastatic subclones with tropism for soft lung tissue in vivo exhibit growth advantages on soft substrates in vitro (Kostic et al, 2009). Based on these results, we hypothesized that the preferential accumulation of OCCs in soft tissues might be due to the intrinsic mechanical properties of the environment.…”