Shake It Up Baby Now: The Changing Focus on TWIST1 and Epithelial to Mesenchymal Transition in Cancer and Other Diseases

Abstract

TWIST1 is a transcription factor that is necessary for healthy neural crest migration, mesoderm development, and gastrulation. It functions as a key regulator of epithelial-to-mesenchymal transition (EMT), a process by which cells lose their polarity and gain the ability to migrate. EMT is often reactivated in cancers, where it is strongly associated with tumor cell invasion and metastasis. Early work on TWIST1 in adult tissues focused on its transcriptional targets and how EMT gave rise to metastatic cells. In recent years, the roles of TWIST1 and other EMT factors in cancer have expanded greatly as our understanding of tumor progression has advanced. TWIST1 and related factors are frequently tied to cancer cell stemness and changes in therapeutic responses and thus are now being viewed as attractive therapeutic targets. In this review, we highlight non-metastatic roles for TWIST1 and related EMT factors in cancer and other disorders, discuss recent findings in the areas of therapeutic resistance and stemness in cancer, and comment on the potential to target EMT for therapy. Further research into EMT will inform novel treatment combinations and strategies for advanced cancers and other diseases.

Keywords: TWIST1; cancer stem cells; drug resistance; epithelial to mesenchymal transition; novel therapies.

Figure 1

Overview of EMT and TWIST1 functions. TWIST1 and the EMT program are required for normal human development, and mutation or loss can lead to developmental syndromes. EMT is activated in cancers, and in addition to migration and metastasis, can also regulate other aspects of tumor progression. Established roles for EMT are shown as faded, while the more recent aspects of EMT, which will be the subject of our review, appear brightly.

Figure 2

Summary of TWIST1, EMT, and cancer therapy. A variety of novel and repurposed therapies targeting TWIST1 and other EMT factors may help alleviate resistance to many current therapies. However, care should be taken to avoid inhibiting EMT in those rare situations where this process actually renders cells sensitive to treatment.

Figure 3

Relationship between EMT and drug responses. As EMT occurs, increased mesenchymal character (M) and loss of epithelial traits (E) often corresponds with increased resistance to a variety of drug classes (blue line). Ovarian cancer exhibits a different response profile, with epithelial, chemoresistant stem cells. There is some evidence that certain breast tumors share the characteristic of drug-sensitive mesenchymal cells, but how closely related these two cancers are remains unclear (orange line).