Mechanotransduction-Induced Reversible Phenotypic Switching in Prostate Cancer Cells

Abstract

Phenotypic plasticity is posed to be a vital trait of cancer cells such as circulating tumor cells, allowing them to undergo reversible or irreversible switching between phenotypic states important for tumorigenesis and metastasis. While irreversible phenotypic switching can be detected by studying the genome, reversible phenotypic switching is often difficult to examine due to its dynamic nature and the lack of knowledge about its contributing factors. In this study, we demonstrate that culturing cells in different physical environments, stiff, soft, or suspension, induced a phenotypic switch in prostate cancer cells via mechanotransduction. The mechanosensitive phenotypic switching in prostate cancer cells was sustainable yet reversible even after long-term culture, demonstrating the impact of mechanical signals on prostate cancer cell phenotypes. Importantly, such a mechanotransduction-mediated phenotypic switch in prostate cancer cells was accompanied by decreased sensitivity of the cells to paclitaxel, suggesting a role of mechanotransduction in the evolution of drug resistance. Multiple signaling pathways such as p38MAPK, ERK, and Wnt were found to be involved in the mechanotransduction-induced phenotypic switching of prostate cancer cells. Given that cancer cells experience different physical environments during disease progression, this study provides useful information about the important role of mechanotransduction in cancer, and how circulating tumor cells may be capable of continuously changing their phenotypes throughout the disease process.

Biophysics of Tumor Microenvironment and Cancer Metastasis - A Mini Review

“…In some cases, individual molecules are responsible when cellular tension in response to ECM rigidity exposes a cryptic signaling molecule or unfolds a propeptide chain; in some other cases, the strain in the cyto-structure can regulate receptor-ligand interaction to affect enzyme activity or, control a mechanosensitive ion channel [ 17 , [23] , [24] , [25] ]. Also, other physical parameters such as change in nuclear volume and shape [ 26 , 27 ], cell membrane curvature [ 28 , 29 ], fluid permeation [ 30 ], plasticity [ 31 , 32 ] etc. play significant roles in different scenarios where physical cues are converted into biochemical responses at a cellular level.…”

Tracking the tumor invasion front using long-term fluidic tumoroid culture

“…Elevated serum levels of GDF15 have been found in metastatic prostate cancer patients and is strongly associated with poor clinical outcome 37 . Furthermore, it has been recently demonstrated that GDF15 expression may be regulated by mechanotransduction and that GDF15 expression increases in palisading cancer cells from xenograft samples 37 , 38 . Together, these suggest that GDF15 expression could be affected by the environment during invasion and may serve as a marker of active invasion.…”

Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective

“…The assembly of these complexes allow for the activation of focal adhesion kinase (FAK) signalling, leading to cytoskeleton contractility and downstream activation of certain transcription factors and thus, gene expression. Studies in epithelial malignancies demonstrate that mechanotransduction can promote cancer cell proliferation, plasticity, chemoresistance, migratory, and metastatic properties and stemness [ 74 , 75 , 76 , 77 , 78 ].…”