STAT3 and epithelial-mesenchymal transitions in carcinomas

Abstract

Cellular programs coupled to cycles of epithelial-mesenchymal transitions (EMTs) play critical roles during embryogenesis, as well as during tissue development, remodeling, and repair. Research over the last decade has established the importance of an ever-expanding list of master EMT transcription factors, whose activity is regulated by STAT3 and function to stimulate the rapid transition of cells between epithelial and mesenchymal phenotypes. Importantly, inappropriate reactivation of embryonic EMT programs in carcinoma cells underlies their metastasis to distant organ sites, as well as their acquisition of stem cell-like and chemoresistant phenotypes operant in eliciting disease recurrence. Thus, targeted inactivation of master EMT transcription factors may offer new inroads to alleviate metastatic disease. Here we review the molecular, cellular, and microenvironmental factors that contribute to the pathophysiological activities of STAT3 during its regulation of EMT programs in human carcinomas.

Keywords: EGFR; EMP; EMT; STAT3; TGF-β; extracellular matrix; metastasis; signal transduction; tumor microenvironment.

Figure 1. The differential modes of STAT3 activation and its genomic and nongenomic functions in responsive cells. (A) The IL-6/IL-6R complex induces dimerization of the common cytokine receptor subunit, gp130 leading the sequential activation of JAK2 and STAT3. (B) OSM binds gp130 and signals through LIF receptor (LIFR)/gp130 heterodimers, or through OSM receptor (OSMR)/gp130 heterodimers to activate JAK2-STAT3. (C) Ligand-activated EGFR forms a molecular complex with STAT3, leading to its activation. (D) FN adhesion induces formation of integrin-EGFR complexes and subsequent EGFR-dependent STAT3 activation. (E) FN-induced cell adhesion is also associated with STAT3 activation via an integrin:Pyk2:JAK2 molecular complex that functions independent of EGFR. (F and G) Tyrosine-phosphorylated STAT3 dimers undergo nuclear translocation (F) where they regulate several “master” EMT transcriptional networks (G). (H) Various miRs discussed in the text either restrict (−) or enhance (+) STAT3 signaling and EMT programs by targeting molecules associated with distinct aspects of the STAT3 pathway. (I) SOCS3 inhibits STAT3 signaling via blockade of upstream signaling through interactions with gp130 and JAK family members. (J) Tyrosine-phosphorylated STAT3 can localize to focal adhesions where it interacts with focal adhesion kinase (FAK) and paxillin, and also regulates the phosphorylation status of the adaptor protein p130Cas. (K) Cytosolic STAT3 also promotes microtubule polymerization by sequestering the microtubule-destabilizing factor stathmin.

Figure 2. Differential modes of STAT3 activation during the metastatic progression of breast cancers. Early during breast cancer development, pre-EMT and nonmetastatic cells that exhibit high levels EGFR expression engage two distinct mechanisms to activate STAT3 signaling pathways, a major axis involving EGF:EGFR (left) and a minor axis regulated by FN-induced formation of β3 integrin-EGFR complexes (middle). Both of these pathways require Src-dependent phosphorylation of EGFR residue Tyr845 located within the catalytic pocket of the kinase domain. As such, both pathways are sensitive to EGFR and Src inhibition. In contrast, post-EMT and metastatic breast cancer cells engage a third mechanism to activate STAT3 that comprises a FN:β1 integrin:Pyk2:JAK2:STAT3 signaling network (right). The activation of this third mechanism may be clinically relevant at sites of secondary pulmonary tumors and likely contributes to the resistance of metastatic breast cancers to EGFR-targeted therapies. Adapted from reference .