A Hybrid Epithelial to Mesenchymal Transition in Ex Vivo Cutaneous Squamous Cell Carcinoma Tissues

Abstract

While most cases of cutaneous squamous cell carcinoma (cSCC) are benign, invasive cSCC is associated with higher mortality and is often more difficult to treat. As such, understanding the factors that influence the progression of cSCC are important. Aggressive cancers metastasize through a series of evolutionary changes, collectively called the epithelial-to-mesenchymal transition (EMT). During EMT, epithelial cells transition to a highly mobile mesenchymal cell type with metastatic capacities. While changes in expression of TGF-β, ZEB1, SNAI1, MMPs, vimentin, and E-cadherin are hallmarks of an EMT process occurring within cancer cells, including cSCC cells, EMT within tissues is not an “all or none” process. Using patient-derived cSCC and adjacent normal tissues, we show that cells within individual cSCC tumors are undergoing a hybrid EMT process, where there is variation in expression of EMT markers by cells within a tumor mass that may be facilitating invasion. Interestingly, cells along the outer edges of a tumor mass exhibit a more mesenchymal phenotype, with reduced E-cadherin, β-catenin, and cytokeratin expression and increased vimentin expression. Conversely, cells in the center of a tumor mass retain a higher expression of the epithelial markers E-cadherin and cytokeratin and little to no expression of vimentin, a mesenchymal marker. We also detected inverse expression changes in the miR-200 family and the EMT-associated transcription factors ZEB1 and SNAI1, suggesting that cSCC EMT dynamics are regulated in a miRNA-dependent manner. These novel findings in cSCC tumors provide evidence of phenotypic plasticity of the EMT process occurring within patient tissues, and extend the characterization of a hybrid EMT program occurring within a tumor mass. This hybrid EMT program may be promoting both survival and invasiveness of the tumors. A better understanding of this hybrid EMT process may influence therapeutic strategies in more invasive disease.

NR5A2 promotes the growth and metastasis of cutaneous squamous cell carcinoma A431 cells via the Wnt/β-catenin signaling pathway

“…In EMT, epithelial cells acquire mesenchymal cell characteristics, giving the cells greater migratory and invasive properties and thus allowing cancer cells to metastasize. 23,24 A previous study reported that NR5A2 knockdown in pancreatic cancer led to an increase in the expression of E-cadherin and a decrease in the expression of Snail and Vimentin, suggesting that NR5A2 is involved in the EMT process. 25 Similar findings were seen in our study, with down-regulation of NR5A2 leading to increased expression of E-cadherin and decreased expression of Snail, Slug, N-cadherin, and Vimentin.…”

NR5A2 promotes malignancy progression and mediates the effect of cisplatin in cutaneous squamous cell carcinoma

“…The role of NR5A2 in EMT has been evaluated in previous research. In EMT, epithelial cells acquire mesenchymal cell characteristics, giving the cells greater migratory and invasive properties, thus allowing the cancer cells to metastasize 26,27 . A previous study reported that NR5A2 knockdown in pancreatic cancer led to an increase in the expression level of E‐cadherin and a decrease in the expression levels of snail and vimentin, suggesting that NR5A2 is involved in the EMT process 28 .…”

Sanguinarine triggers apoptosis in cutaneous squamous cell carcinoma cells through ROS-dependent JNK-kinase signaling

“…During normal physiological processes such as wound healing, EMT is integral in restoring epithelial and endothelial integrity. In epithelial-derived malignancies, however, EMT plasticity has been proposed as the critical mechanism for the acquisition of mesenchymal traits by epithelial cells, which gain migratory and/or invasive properties [55]. Cells exhibiting EMT characteristics have been shown to impart changes in the extracellular matrix (ECM) composition and modify cell-ECM and cell-cell interactions via the secreted zinc-endopeptidases MMPs, thus enhancing cell migration [56,57].…”