Actomyosin tension as a determinant of metastatic cancer mechanical tropism

Abstract

Despite major advances in the characterization of molecular regulators of cancer growth and metastasis, patient survival rates have largely stagnated. Recent studies have shown that mechanical cues from the extracellular matrix can drive the transition to a malignant phenotype. Moreover, it is also known that the metastatic process, which results in over 90% of cancer-related deaths, is governed by intracellular mechanical forces. To better understand these processes, we identified metastatic tumor cells originating from different locations which undergo inverse responses to altered matrix elasticity: MDA-MB-231 breast cancer cells that prefer rigid matrices and SKOV-3 ovarian cancer cells that prefer compliant matrices as characterized by parameters such as tumor cell proliferation, chemoresistance, and migration. Transcriptomic analysis revealed higher expression of genes associated with cytoskeletal tension and contractility in cells that prefer stiff environments, both when comparing MDA-MB-231 to SKOV-3 cells as well as when comparing bone-metastatic to lung-metastatic MDA-MB-231 subclones. Using small molecule inhibitors, we found that blocking the activity of these pathways mitigated rigidity-dependent behavior in both cell lines. Probing the physical forces exerted by cells on the underlying substrates revealed that though force magnitude may not directly correlate with functional outcomes, other parameters such as force polarization do correlate directly with cell motility. Finally, this biophysical analysis demonstrates that intrinsic levels of cell contractility determine the matrix rigidity for maximal cell function, possibly influencing tissue sites for metastatic cancer cell engraftment during dissemination. By increasing our understanding of the physical interactions of cancer cells with their microenvironment, these studies may help develop novel therapeutic strategies.

Fluid shear stress stimulates breast cancer cells to display invasive and chemoresistant phenotypes while upregulating PLAU in a 3D bioreactor

“…Given that mechanotransduction can modulate cellular responses to anti‐neoplastic agents (Ip et al, ; McGrail, Kieu, & Dawson, ; McGrail, Kieu, Iandoli, & Dawson, ), breast cancer cells were treated with 25 µM paclitaxel for 72 hr. Chemotherapy treatment was administered at the previously determined IC 50 concentration of 25 µM (Chen et al, ; Sarkar & Kumar, ).…”

Esophageal Cancer Development: Crucial Clues Arising from the Extracellular Matrix

“…Moreover, cellular responses to mechanical stimuli also alter gene expression. For example, the expression of integrins, MMPs, and also cytoskeletal proteins are all increased in response to stiff substrates in a sort of positive feedback that enhances tumor progression and metastasis [68][69][70]. Although most of the mechanical mechanisms described above are already partially elucidated for some cancers, very little is known about these phenomena in EC.…”

The predictive link between matrix and metastasis

“…One example recently shown by Sheetz and colleagues used simple control of mechanics to report that MDA-MB-231 variant cells proliferate in vitro on materials mechanically similar to the tissue to which they metastasize to in vivo , (Figure 2, [2]). This work was reproduced in a comparative study between ovarian and breast cancer cells (Figure 2, [4]). These examples suggest that physical features may filter for populations of breast cancer cells that exhibit enhanced proliferative ability at specific secondary tissue sites, and that biomaterial platforms with controlled mechanics could be used to identify this proliferative capacity in vitro .…”

“…a) Cells that metastasized to bone and lung in vivo shared similar in vitro motility characteristics, adapted from Kostic et al [2]. b) Mechanosensitivity can be used to distinguish between breast cancer metastatic cells (MDA-MB-231) and ovarian cancer metastatic cells (SKOV-3), from McGrail et al [4]. c) Barney et al developed an in vitro screen that used integrin-binding to predict in vivo metastasis to the bone, brain, and lung, as well as identify integrin subunits as tissue-specific risk factors [1] ADD REFERENCE.…”