High expression of oxidative phosphorylation genes predicts improved survival in squamous cell carcinomas of the head and neck and lung.

Mitochondrial activity is a critical component of tumor metabolism, with profound implications for tumorigenesis and treatment response. We analyzed clinical, genomic and expression data from patients with oral cavity squamous cell carcinoma (OCSCC) in order to map metabologenomic events which may correlate with clinical outcomes and identified nuclear genes involved in oxidative phosphorylation and glycolysis (OXPHOG) as a critical predictor of patient survival. This correlation was validated in a secondary unrelated set of lung squamous cell carcinoma (LUSC) and was shown to be driven largely by over-expression of nuclear encoded components of the mitochondrial electron transport chain (ETC) coordinated with an increase in tumor mitochondrial DNA copy number and a strong threshold effect on patient survival. OCSCC and LUSC patients with a favorable OXPHOG signature demonstrated a dramatic (>2fold) improvement in survival compared to their counterparts. Differential OXPHOG expression correlated with varying tumor immune infiltrates suggesting that the interaction between tumor metabolic activity and tumor associated immunocytes may be a critical driver of improved clinical outcomes in this patient subset. These data provide strong support for studies aimed at mechanistically characterizing the interaction between tumor mitochondrial activity and the tumor immune microenvironment.

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma.

Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1's role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer's genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.