Twist1 Is a Key Regulator of Cancer-Associated Fibroblasts

Abstract

Cancer-associated fibroblasts (CAF) are key contributors to malignant progression, but their critical regulators remain largely unknown. In this study, we examined the role of Twist1, a central regulator of epithelial–mesenchymal transition in carcinoma cells, in the transdifferentiation of normal quiescent fibroblasts to CAF and we defined its upstream controls and downstream effectors. Primary human gastric fibroblast and CAF cultures were established from gastrectomy specimens and validated as nontumor cells by somatic mutation analyses. In these cultures, exposure to the proinflammatory cytokine IL6 commonly expressed in tumors was sufficient to induce Twist1 expression in normal fibroblasts and transdifferentiate them into CAFs via STAT3 phosphorylation. In xenograft models, tumor infiltration of Twist1-expressing CAFs was enhanced strongly by ectopic IL6 expression in gastric or breast cancer cells. We found that Twist1 expression was necessary and sufficient for CAF transdifferentiation. Enforced expression of Twist1 in normal fibroblasts was also sufficient to drive CAF marker expression and malignant character in gastric cancer cells both in vitro and in vivo. Conversely, silencing the expression of Twist1 in CAFs abrogated their tumor-promoting properties. Downstream of Twist1, we defined the chemokine CXCL12 as a transcriptional target. Clinically, CXCL12 and Twist1 expression were correlated in CAFs present in gastric tumor specimens. Finally, ectopic expression of Twist1 in normal fibroblasts suppressed premature senescence, whereas Twist1 attenuation accelerated senescence in CAFs. Our findings define Twist1 as a compelling target to deprogram the tumor-supporting features of the cancer microenvironment. Cancer Res; 75(1); 73–85. ©2014 AACR.

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

“…Interestingly, the authors noted that the mechanotransduction pathways regulating TWIST1 were, like SNAIL1, distinct from YAP regulation. In that work, CAFs were not examined; however, another report studying gastric cancer CAFs has found that TWIST1 is important for the differentiation of normal tissue fibroblasts into CAFs (Lee et al, 2015). We also noted that TWIST1 protein levels increased as fibroblasts evolved from normal tissue fibroblasts to CAFs (Fig.…”

Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment

“…Through CXCR4, a receptor of CXCL12, signaling pathway in cancer cells, secretion of CXCL12 by CAFs induces epithelial-mesenchymal transition of cancer cells in gastric and prostate cancers [18][19], migration and metastasis in prostate cancer [20], and tumor growth in breast cancer [21].…”

Cancer-associated fibroblasts: A multifaceted driver of breast cancer progression

“…mCAFs, especially those isolated from the interface zone of breast tumors, are claimed to be a robust inducer of EMT [94,95]. With respect to the molecular mechanism, many mediators, such as Twist1 [96], SDF-1 [97] and the SNAIL family [51], were identified. Cycloxygenase-2 (COX-2)/nuclear factor-kappa B (NFκB)/hypoxiainducible factor-1 (HIF-1) signaling, and TGFβ, ERK, JUN and RHO signaling are thought to be responsible for mCAF-induced EMT [68,94,95,[98][99][100].…”