Publications

The cellular microenvironment is highly heterogeneous and dynamic. Therefore, cells must be equipped with molecular tools to adapt and respond to constantly fluctuating inputs. One such input is mechanical force, which activates signalling and regulates cell behaviour in the process of mechanotransduction. Whereas the mechanisms activating mechanotransduction are well studied, the reversibility of this process, whereby cells disassemble and reverse force-activated signalling pathways upon cessation of mechanical stimulation is far less understood. In this review we will outline some of the key experimental techniques to investigate the reversibility of mechanical signalling, and key discoveries arising from them.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

JTD Keywords: mechanical memory, memory, reversibility, Mechanical memory, Mechanotransduction, Nuclear, Reversibility

Lung cancer is the leading cause of cancer-related death worldwide. The desmoplastic stroma of lung cancer and other solid tumors is rich in tumor-associated fibroblasts (TAFs) exhibiting an activated/myofibroblast-like phenotype. There is growing awareness that TAFs support key steps of tumor progression and are epigenetically reprogrammed compared to healthy fibroblasts. Although the mechanisms underlying such epigenetic reprogramming are incompletely understood, there is increasing evidence that they involve interactions with either cancer cells, pro-fibrotic cytokines such as TGF-β, the stiffening of the surrounding extracellular matrix, smoking cigarette particles and other environmental cues. These aberrant interactions elicit a global DNA hypomethylation and a selective transcriptional repression through hypermethylation of the TGF-β transcription factor SMAD3 in lung TAFs. Likewise, similar DNA methylation changes have been reported in TAFs from other cancer types, as well as histone core modifications and altered microRNA expression. In this review we summarize the evidence of the epigenetic reprogramming of TAFs, how this reprogramming contributes to the acquisition and maintenance of a tumor-promoting phenotype, and how it provides novel venues for therapeutic intervention, with a special focus on lung TAFs.

JTD Keywords: cancer-associated fibroblasts, desmoplasia, dna methylation, epigenetics, expression, genomic dna, lung cancer, mechanical memory, myofibroblast differentiation, pulmonary fibroblasts, smoking, stromal fibroblasts, tgf-?, tgf-beta, tgf-β, transforming growth-factor-beta-1, tumor stroma, Cancer-associated fibroblasts, Carcinoma-associated fibroblasts, Desmoplasia, Epigenetics, Lung cancer, Smoking, Tgf-β, Tumor stroma