Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts

Abstract

Increased deposition of collagen in extracellular matrix (ECM) leads to increased tissue stiffness and occurs in breast tumors. When present, this increases tumor invasion and metastasis. Precisely how this deposition is regulated and maintained in tumors is unclear. Much has been learnt about mechanical signal transduction in cells, but transcriptional responses and the pathophysiological consequences are just becoming appreciated. Here, we show that the SNAIL1 (also known as SNAI1) protein level increases and accumulates in nuclei of breast tumor cells and cancer-associated fibroblasts (CAFs) following exposure to stiff ECM in culture and in vivo. SNAIL1 is required for the fibrogenic response of CAFs when exposed to a stiff matrix. ECM stiffness induces ROCK activity, which stabilizes SNAIL1 protein indirectly by increasing intracellular tension, integrin clustering and integrin signaling to ERK2 (also known as MAPK1). Increased ERK2 activity leads to nuclear accumulation of SNAIL1, and, thus, avoidance of cytosolic proteasome degradation. SNAIL1 also influences the level and activity of YAP1 in CAFs exposed to a stiff matrix. This work describes a mechanism whereby increased tumor fibrosis can perpetuate activation of CAFs to sustain tumor fibrosis and promote tumor metastasis through regulation of SNAIL1 protein level and activity.

Past matrix stiffness primes epithelial cells and regulates their future collective migration through a mechanical memory

“…7b), as described previously [18, 31]. We found that the leading-edge migration speed of stiff-primed YAP-KD cells was ~15μm/h on a soft secondary ECM, which was similar to the control case of homogeneously soft ECM (Fig.…”

“…7). Previously, we have shown that YAP-depleted CAFs maintain the mechano-sensitive SNAIL1 protein level [18], which indicates that the cells are able to adopt alternate YAP-independent pathways for sensing matrix stiffness.…”

“…As cells pass through a tissue microenvironment, a distinct set of mechanosensitive signaling events occur [1], such as clustering of integrin-based adhesion proteins into focal adhesions [14], Rho-ROCK activation [15, 16], and nuclear localization of transcriptional regulators YAP and SNAIL1 [17, 18]. Recently, mechanical dosing of human mesenchymal stem cells on matrices of tunable stiffness has been found to regulate mechanical memory-dependent lineage commitment decisions, and this process is shown to depend on YAP activity [19].…”

Epithelial‐to‐mesenchymal transition transcription factors in cancer‐associated fibroblasts

“…Increased ERK2 activity leads to nuclear accumulation of Snail1, and thus to avoidance of cytosolic proteasomal degradation (Zhang et al ., ). This mechanism, which increases in tumour fibrosis, can perpetuate activation of CAFs to sustain tumour fibrosis and to promote tumour metastasis through the regulation of Snail1 protein level and activity (Baulida and García de Herreros, ; Zhang et al ., ).…”

Tissue Force Programs Cell Fate and Tumor Aggression

“…Interestingly, a subsequent study found that TWIST1 controls tumor cell maintenance and survival independently of its EMT function, raising doubts about the role of EMT in invasion and metastasis in this context (103). However, ECM stiffness was shown to stabilize the nuclear accumulation of the EMT transducer, Snail Family Transcriptional Repressor 1 (SNAIL1) in breast cancer associated fibroblasts through ROCK and ERK2 activation, and a fibrogenic response was dependent on this mechanotransduction pathway (104). These data suggest that mechanical stresses can trigger the activity of EMT transcriptional regulators to support tumor fibrosis, tumor cell survival and invasion.…”