The interplay between physical cues and mechanosensitive ion channels in cancer metastasis

Abstract

Physical cues have emerged as critical influencers of cell function during physiological processes, like development and organogenesis, and throughout pathological abnormalities, including cancer progression and fibrosis. While ion channels have been implicated in maintaining cellular homeostasis, their cell surface localization often places them among the first few molecules to sense external cues. Mechanosensitive ion channels (MICs) are especially important transducers of physical stimuli into biochemical signals. In this review, we describe how physical cues in the tumor microenvironment are sensed by MICs and contribute to cancer metastasis. First, we highlight mechanical perturbations, by both solid and fluid surroundings typically found in the tumor microenvironment and during critical stages of cancer cell dissemination from the primary tumor. Next, we describe how Piezo1/2 and transient receptor potential (TRP) channels respond to these physical cues to regulate cancer cell behavior during different stages of metastasis. We conclude by proposing alternative mechanisms of MIC activation that work in tandem with cytoskeletal components and other ion channels to bestow cells with the capacity to sense, respond and navigate through the surrounding microenvironment. Collectively, this review provides a perspective for devising treatment strategies against cancer by targeting MICs that sense aberrant physical characteristics during metastasis, the most lethal aspect of cancer.

Three-dimensional matrix stiffness modulates mechanosensitive and phenotypic alterations in oral squamous cell carcinoma spheroids

“…Additionally, TRPV4 can also promote matrix stiffness-induced EMT. 20,30 Interestingly, the Piezo1 gene was not found to be significantly differentially expressed between the soft and stiff matrix conditions. Several genes reported to have associations with Piezo1 activity including DKK3, OBSCN, TNNT1, MAPK-10, -15, and -BP1 were, however, found to be upregulated in the stiff matrix groups.…”

“…Both these genes are associated with malignant progression with EDN2 involved in tumorigenesis and VIM playing a role in cell attachment, migration, and metastasis. 20 Certain other genes such as MAPK3, RAC3, JAK3, and Rho-GTPases RHOG and RHOD with associations to cancer-promoting signals were also found to be upregulated in stiff hydrogel spheroids. 43,44 Stiff substrate groups also indicated the presence of common EMT-associated genes in cancer such as CD44, COL5A3, SERPINE1, LAMC2, TGFB1, CDH13, SPARC, and certain integrins.…”

Prognostic value of tumor necrosis based on the evaluation of frequency in invasive breast cancer

“…Fourth, this study reveals that collagen, which hitherto is ignored in pathology diagnostics for breast cancer, exhibits distinctive spatial location features in histologic patterns of TN that may inform the relevant underlying processes of breast cancer development. Studies have shown that collagen in the extracellular matrix (ECM) provides biophysical cues which can influence breast cancer progression and metastasis [ 40 ]. Collagen deposition during breast cancer progression contributes to increased matrix stiffness or elasticity, which establishes migration paths for cells.…”

“…Collagen deposition during breast cancer progression contributes to increased matrix stiffness or elasticity, which establishes migration paths for cells. Accordingly, elevated collagen and the collagen fiber alignment relative to the breast tumor interface are risk factors for breast cancer [ 40 ]. These results indicate that the compressive stress in the tumor interior can influence the shape of the tumor mass and then influence the topographical features of the ECM, such as the formation of different spatial arrangements of collagen, which provide clues to the prognosis of breast cancer.…”

Advances in cancer mechanobiology: Metastasis, mechanics, and materials

“…1 ). 7 Mechanical forces are transduced through mechanoreceptors which then affect cellular processes, such as proliferation and differentiation, well reviewed by Bera et al 8 Specifically, mechanical cues alter cell morphology, cell–cell interaction, and cell signaling and facilitate epithelial to mesenchymal transition (EMT) and other migratory programming. 9,10 Forces within the tumor microenvironment (TME) can be broken down and simplified into three categories: (i) shear stress, (ii) tension and strain, and (iii) solid stress and compression ( Fig.…”