Transglutaminase as a Driver of Aggressive Squamous Cell Carcinoma

Abstract

Non-melanoma skin cancer is the most common cancer in human populations. Cutaneous squamous cell carcinoma (cSCC) is extremely frequent and is the most common cancer capable of metastasis. cSCC is primarily linked to exposure to ultraviolet (UV) radiation. Immunosuppressed patients are two-hundred times more likely to get metastatic SCC. Moreover, environmental irritants and increased exposure to UV irradiation with indoor tanning have led to increased skin cancer incidence. Thus, skin cancer is an important health concern. It is thought that a small fraction of tumor stem cells possess the ability to initiate and sustain tumor growth. These cells, referred to as cancer stem cells (CSC) possess traits of normal stem cells and are slow-cycling, capable of self-renewal through asymmetrical division, and are able to give rise to all the cell types in the tumor population. Bulk tumor cells represent the majority of the tumor mass, but in contrast to cancer stem cells, are dispensable for tumor propagation. Thus, therapeutic targeting of cancer stem cell survival mechanisms is an important cancer therapy strategy. Herein we provide evidence that transglutaminase type 2 (TG2) is a key controller of epidermal cancer stem cells (ECS cell) survival and an important therapeutic target. TG2 is a multifunctional member of the transglutaminase family of proteins. In the closed conformation, which exists in cells, TG2 functions as a GTP binding/G protein-related signaling protein. A rise in intracellular calcium concentration shifts TG2 to an open conformation that functions in cell and matrix remodeling. TG2 has been shown to be elevated in a number of metastatic cancers, but its role in disease progression and survival is not well characterized. We show that TG2 is constitutively expressed in ECS cells where it facilitates migration, invasion, spheroid formation and survival of ECS cells. Mechanistic studies, using TG2 mutants, revealed that the GTP-binding activity is required for maintenance of ECS cell growth and survival. Furthermore, signaling analysis showed that TG2 is involved in regulating several key pathways involved in stemness and metastasis, including EMT and Hippo signaling. These studies suggest TG2 is an important therapeutic target for invasive and metastatic cSCC.