Partial EMT in head and neck cancer biology: A spectrum instead of a switch

Partial EMT in head and neck cancer biology: A spectrum instead of a switch

Abstract

Our understanding of epithelial-to-mesenchymal transition has slowly evolved from a simple two state, binary model to a multi-step, dynamic continuum of epithelial-to-mesenchymal plasticity, with metastable intermediate transition states that may drive cancer metastasis. Head and neck cancer is no exception, and in this review, we use head and neck as a case study for how partial-EMT cell states may play an important role in cancer progression. In particular, we summarize recent in vitro and in vivo studies that uncover these intermediate transition states, which exhibit both epithelial and mesenchymal properties and appear to have distinct advantages in migration, survival in the bloodstream, and seeding and propagation within secondary metastatic sites. We then summarize the common and distinct regulators of p-EMT as well as methodologies for identifying this unique cellular subpopulation, with a specific emphasis on the role of cutting-edge technologies, such as single cell approaches. Finally, we propose strategies to target p-EMT cells, highlighting potential opportunities for therapeutic intervention to specifically target the process of metastasis. Thus, although significant challenges remain, including numerous gaps in current knowledge, a deeper understanding of EMT plasticity and a genuine identification of EMT as spectrum rather than a switch will be critical for improving patient diagnosis and treatment across oncology.

INTRODUCTION

Metastasis is a complex, multistep process whereby primary cancer cells disseminate to regional or distant secondary sites, resulting in substantial patient morbidity and death across numerous solid malignancies. Although the biological basis of metastasis has been extensively investigated, the mechanisms that trigger metastasis remain poorly understood.

Among carcinomas -- those tumors derived from the epithelium -- one compelling mechanism that has garnered interest is epithelial-to-mesenchymal transition. In this conceptual framework of metastasis, malignant cells absolve their epithelial identity and adopt a mesenchymal expression state, thereby becoming more motile as they are imbued with the capacity to remodel the extracellular matrix and invade local tissues, ultimately entering and exiting the circulation to seed distant colonies. Early studies of EMT and cancer suggested EMT was akin to a switch, with cells ostensibly in an epithelial or mesenchymal state and mesenchymal cells representing the infiltrative subpopulation of a tumor. By contrast, intermediary states adopted by cells as they underwent EMT were considered to be incidental, inconsequential, and entirely transient.

However, it is now widely agreed that EMT is a complex and dynamic cell biologic process, with cells existing in a number of meta-stable, intermediary states between the epithelial and mesenchymal poles (so-called "hybrid-EMT" or "partial-EMT" states). These partial-EMT cells may invade collectively via oligocellular clusters, maintaining some cell-to-cell adhesive properties while escaping from the stromal scaffold and remodeling the extracellular matrix. Indeed, partial-EMT cells are now believed to play essential roles in local tissue invasion, collective migration, circulating tumor cells, and, ultimately, both locoregional and distant metastases. Importantly, these aggressive biological features have clinical implications including treatment resistance and effects on overall survival. The partial-EMT cell state is driven both by intrinsic genetic, epigenetic, and post-translational alterations among primary malignant cells as well as paracrine signaling via supportive stromal cells in the tumor microenvironment. Clearly, the identification of partial-EMT represents an important aspect of EMT biology that continues to mature within oncology, yet much remains unknown.

In this review, we discuss the importance of partial-EMT in tumor progression and metastasis and the evolving landscape regarding EMT plasticity, utilizing head and neck squamous cell carcinoma as a case study for this discussion. Identification of a hybrid partial-EMT state and its distinction from completely transformed mesenchymal or epithelial cells represents the first and most important step in improving our understanding of these new cell states. We then describe markers that help identify partial-EMT cells, while also exploring the important drivers and regulators of partial-EMT and potential strategies to target this expression state. Finally, we discuss the challenges that remain in studying partial-EMT and the opportunities for new therapeutics targeting this essential program.