Metabolic adaptation enables cisplatin resistance and inhibits tumor immunity

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Head and neck squamous cell carcinoma (HNSCC) remains a leading cause of cancer death worldwide, with ~500,000 cases/year. Cisplatin is the gold standard systemic agent for HNSCC. Cisplatin resistance, both intrinsic and acquired, has been described in preclinical models and is frequently encountered in clinical practice; when it occurs, it is deadly. The overarching goal of the Houston Center for Acquired Resistance Research (H-CARR) is to develop a robust biological understanding of the key drivers of cisplatin resistance in HNSCC, which will lead to the development of novel means of early detection of resistant tumors and treatment. We previously showed that acetate metabolism and neuronal signaling are essential to organizing the metabolic response to cisplatin-generated stress. H-CARR will bring together our biological and metabolic models of cisplatin resistance to provide a comprehensive window into its acquisition, as outlined in the projects listed below. Project 1 will use state-of-the-art metabolomic studies to identify the critical metabolic dependencies of cisplatin-resistant HNSCC, identify opportunities for effective metabolic inhibition, and improve our understanding of the crosstalk between the acquisition of cisplatin resistance and modulation of the tumor immune microenvironment. Project 2 will explore the genomic and transcriptomic reprogramming required to sustain the metabolic shifts that accompany the development of resistance through intrinsic cellular mechanisms and paracrine signaling between tumor cells and adrenergic neurons. Project 3 will test whether the metabolic reprogramming outlined in Project 1 is detectable via non-invasive imaging (hyperpolarized magnetic resonance imaging) and whether the biological shifts outlined in Project 2 due to clonal extinction and expansion can be detected by CTC analysis in patients undergoing cisplatin-based treatment. In the proposed supplement, we aim to foster new collaborations and deepen our understanding of the neuron-dependent metabolic shifts that drive cisplatin resistance in HNSCC. These studies will increase the overall impact of Projects 1 and 2 within the original scope by identifying actionable paracrine signaling between tumor cells and the neurons associated with metabolic changes and cisplatin resistance. H-CARR has the potential to realize the full clinical utility of cisplatin by identifying resistance early in treatment and developing the means to overcome resistance and phenotypes associated with resistance, such as enhanced distant metastasis. Successful completion of the proposed experiments will generate the new clinical standard for precision oncology approaches to the clinical utilization of cisplatin in HNSCC and related upper-aerodigestive tract cancers; therefore, it will have a major impact on cancer survival worldwide.