Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis

Abstract

The oncogenic epithelial-mesenchymal transition (EMT) contributes to tumor progression in various context-dependent ways, including increased metastatic potential, expansion of cancer stem cell subpopulations, chemo-resistance and disease recurrence. One of the hallmarks of EMT is resistance of tumor cells to anoikis. This resistance contributes to metastasis and is a defining property not only of EMT but also of cancer stem cells. Here, we review the mechanistic coupling between EMT and resistance to anoikis. The discussion focuses on several key aspects. First, we provide an update on new pathways that lead from the loss of E-cadherin to anoikis resistance. We then discuss the relevance of transcription factors that are crucial in wound healing in the context of oncogenic EMT. Next, we explore the consequences of the breakdown of cell-polarity complexes upon anoikis sensitivity, through the Hippo, Wnt and transforming growth factor β (TGF-β) pathways, emphasizing points of crossregulation. Finally, we summarize the direct regulation of cell survival genes through EMT-inducing transcription factors, and the roles of the tyrosine kinases focal adhesion kinase (FAK) and TrkB neurotrophin receptor in EMT-related regulation of anoikis. Emerging from these studies are unifying principles that will lead to improvements in cancer therapy by reprogramming sensitivity of anoikis.

Fig. 1.

EMT programs anoikis resistance. Mechanisms that connect these phenomena are discussed in this Commentary. The intercellular bridge protein depicted in this diagram is a generalized intercellular component of junctional complexes (e.g. E-cadherin, desmoplakin, desmoglein, claudin) and a generalized cytoplasmic or cytoskeletal element is shown transducing its signals.

Fig. 2.

E-cadherin and ankyrin-G are lost coordinately during EMT, conferring anoikis resistance. This occurs because the ankyrin-G-interacting protein NRAGE is no longer sequestered by ankyrin-G. This, in turn, permits translocation of NRAGE to the nucleus, where it forms a repressor/co-repressor complex with TBX2, thereby blocking the expression of the p14ARF gene (CDKN2A) and attenuating anoikis.

Fig. 3.

The epithelial specific cell polarity proteins and maintain anoikis sensitivity by regulating the Hippo, Wnt and TGF-β pathways. In normal, interacting epithelial cells (left panel), the cell polarity complexes, crumbs (Crb) and scribble (Scrib) stimulate the phosphorylation of YAP and TAZ through the LATS kinase. This maintains YAP and TAZ in the cytoplasm, sensitizing cells to anoikis. In addition, cytoplasmic YAP and TAZ interact with Smad3 and prevent its nuclear translocation, even in the presence of active TGF-β receptors. Furthermore, cytoplasmic TAZ interacts with disheveled (Dsh), inhibiting canonical Wnt signaling. Expression or activation of CTBP; ZEB1/2,Snail, Twist, FAK, ILK, NF-κB or TrkB induce EMT (right panel), which – in turn – compromises cell polarity complexes, promotes the nuclear translocation of YAP, TAZ and Smad3, and induces expression of cell survival genes. The absence of cytoplasmic TAZ allows Dsh to be activated by CK1, which inhibits glycogen synthase kinase 3 β (GSK3β), thus allowing β-catenin to transactivate pro-survival genes in the nucleus. Alternatively, the Akt–GSK3β–β-catenin axis can be stimulated through activation of TrkB.