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

Abstract

Beyond inducing epithelial-to-mesenchymal transcription (EMT), transcriptional factors of the Snail, ZEB and Twist families (EMT-TFs) control global plasticity programmes affecting cell stemness and fate. Literature addressing the reactivation of these factors in adult tumour cells is very extensive, as they enable cancer cell plasticity and fuel both tumour initiation and metastatic spread. Incipient data reveal that EMT-TFs are also expressed in fibroblasts, providing these with additional properties. Here, I will review recent reports on the expression of EMT-TFs in cancer-associated fibroblasts (CAFs). The new model suggests that EMT-TFs can be envisioned as essential metastasis and chemoresistance-promoting molecules, thereby enabling coordinated plasticity programmes in parenchyma and stroma-tumour compartments.

Keywords: ZEB; Snail; Twist; cancer-associated fibroblasts; epithelial-to-mesenchymal transition transcription factors; tumour-stroma crosstalk.

Figure 1

Paracrine signalling and mechanical signalling generated by CAFs in an EMT‐TF‐dependent manner promote the expression of EMT‐TFs in cancer epithelial cells. (A) Tissue homeostasis in mammary glands is maintained by a coordinated signalling between epithelial cells (yellow) and stromal cells (orange). Oncogenic mutations in epithelial cells fuel uncontrolled epithelial growth, generating primary tumour foci (purple cells). Paracrine signalling from tumour cells (orange arrow in the magnified box) promotes the expression of nuclear EMT‐TFs in adjacent fibroblasts (red nuclei). Additional colour coding: luminal cells, yellow nuclei; basal epithelial cells, green nuclei; normal fibroblasts, orange nuclei; basal lamina; red lines; extracellular fibres, blue lines. (B) In metastatic tumours, basal lamina is hampered and tumour cells escape from primary foci (dark purple cells). These events are facilitated by desmoplasia, microenvironmental changes promoted by CAFs expressing EMT‐TFs (orange cells with red nuclei), including fibrillar architecture and secretome remodelling (orange arrows and text in the amplified box). Signalling generated by local extracellular changes (black arrows) induces the expression of EMT‐TFs in adjacent tumour cells (dark violet cells with red nuclei), providing them with properties related to cancer malignance, such as stemness, increased tumour cell motility and chemoresistance. Therefore, EMT‐TFs induce changes in cell behaviour in both parenchymal and stromal tumour cells that support poor cancer prognosis.

Figure 2

Putative EMT‐TF‐dependent mechanisms supporting CAF phenotype. The reported activities of EMT‐TFs in CAFs and other cells allow elucidation of EMT‐TF‐dependent mechanisms controlling CAF phenotype. (A) Putative EMT‐TF downstream mechanisms driving CAF activation are schematized. Snail1 and ZEB1 facilitate assembly and activity of the contractile cytoskeleton by modulating RhoA activity and αSMA transcription, respectively. Both proteins can interact with and modulate YAP1 activity, which controls regulatory molecules of the CAF cytoskeleton, such as ANLN, DIAPH3, and MYL9. Twist1 acts on the cytoskeletal protein palladin. On the other hand, extracellular molecules such as fibronectins, collagens, crosslinking enzymes or metalloproteases are targeted by the Snail, ZEB or Twist proteins. Through these pathways, EMT‐TFs regulate the CAF cytoskeleton assembly and activity and modify extracellular mechanics. Snail1 and Twist1 are also implicated in the secretion of soluble factors by CAFs, such as CXCL12, MCP‐3 and PGE2. (B) EMT‐TFs are likely to be central regulators of feed‐forward molecular loops that set the CAF phenotype. Twist1 induces an autoactivatory loop in TGF‐β signalling that prolongs the action of the cytokine on fibroblasts. Snail1, YAP1 and Twist1 are activated by extracellular rigidity generated by CAFs, allowing a mechanosensitive feed‐forward regulation of the CAF phenotype. YAP1 can also fuel TGF‐β‐induced EMT‐TF activity and favours ZEB1‐dependent transcription. Interactions between Snail1/2 and ZEB1 with YAP1 can further potentiate their activity. (C) The in/out and out/in EMT‐TF‐dependent mechanisms described in (A) and (B) that collectively sustain the CAF phenotype are represented.