Molecular dissection of the oncogenic role of ETS1 in the mesenchymal subtypes of head and neck squamous cell carcinoma

Abstract

Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous disease of significant mortality and with limited treatment options. Recent genomic analysis of HNSCC tumors has identified several distinct molecular classes, of which the mesenchymal subtype is associated with Epithelial to Mesenchymal Transition (EMT) and shown to correlate with poor survival and drug resistance. Here, we utilize an integrated approach to characterize the molecular function of ETS1, an oncogenic transcription factor specifically enriched in Mesenchymal tumors. To identify the global ETS1 cistrome, we have performed integrated analysis of RNA-Seq, ChIP-Seq and epigenomic datasets in SCC25, a representative ETS1 ^high mesenchymal HNSCC cell line. Our studies implicate ETS1 as a crucial regulator of broader oncogenic processes and specifically Mesenchymal phenotypes, such as EMT and cellular invasion. We found that ETS1 preferentially binds cancer specific regulator elements, in particular Super-Enhancers of key EMT genes, highlighting its role as a master regulator. Finally, we show evidence that ETS1 plays a crucial role in regulating the TGF-β pathway in Mesenchymal cell lines and in leading-edge cells in primary HNSCC tumors that are endowed with partial-EMT features. Collectively our study highlights ETS1 as a key regulator of TGF-β associated EMT and reveals new avenues for sub-type specific therapeutic intervention.

Author summary

The expression of the transcriptional regulator, E26 transformation-specific 1 (ETS1), is elevated in many epithelial cancers and portends aggressive tumor behavior and poor survival. Within these carcinomas, ETS1 function has been shown to be associated with a wide range of cellular responses that include increased proliferation, angiogenesis, metastasis and drug resistance. Here we focus on Head and Neck Squamous Cell Carcinoma (HNSCC) and discover that higher expression of ETS1 is specifically more pronounced in the mesenchymal subtypes of HNSCC, which represent tumors with enriched expression of Epithelial to Mesenchymal Transition (EMT) markers and inflammation. By using genomic and epigenomic strategies, we have identified the global targets of ETS1 in a preclinical Mesenchymal HNSCC cell model and determined the crucial gene network that is most dependent upon its function. We further validate this ETS1-driven gene expression signature within several HNSCC patient derived datasets and conclude that ETS1 acts as a crucial regulator of the TGFβ signaling cascade to drive EMT. Our findings reinforce the challenges of epithelial tumor heterogeneity and offer insights into molecular underpinning of a specific subtype that can be mined for cancer vulnerability.