Integrative Multi-Omics of Metabolomics and Epigenetics to Explore thePathophysiology of Cachexia and Survival in Head and Neck SquamousCell Carcinoma

Cachexia is a common and lethal syndrome affecting up to 80% of patients with advanced cancer, responsible for approximately 30% of all cancer-related deaths. Despite being a significant factor that worsens patient outcomes, cachexia remains one of the most under-recognized and undertreated complications in cancer care. It results in severe muscle wasting, weight loss, inflammation, and profound fatigue, significantly reducing patients' quality of life and response to treatment. In head and neck squamous cell carcinoma (HNSCC), cachexia affects 40-50% of patients, leading to a median survival of just 13 months, which is only one-fifth of the survival time seen in non-cachexic patients. Cachexia remains poorly understood, and there is currently no approved treatment that effectively reverses this condition. Current management strategies, such as nutritional support and exercise, are largely ineffective and hope only to halt the condition, not reverse it. The effects of patient outcomes and lack of treatment options highlight the urgent need for a deeper understanding of the early biological mechanisms of cachexia to identify opportunities for timely intervention. Recent preclinical studies indicate that cachexia is driven by early systemic dysfunctions involving tightly interconnected metabolic, immune, and inflammatory pathways. These complex interactions create a vicious cycle that accelerates disease progression, highlighting the need for a comprehensive approach to understanding the systemic nature of cachexia. To address the shortcomings of prior human cachexia research, which focused mainly on isolated pathways, we propose an integrated multiomics approach to comprehensively explore these systemic mechanisms in HNSCC patients. By investigating plasma metabolomics, DNA methylation of circulating white blood cells, and inflammatory cytokines, we aim to identify key biomarkers and mechanisms driving weight loss, cachexia progression, and survival. Leveraging an existing cohort of over 200 HNSCC patients with comprehensive pretreatment and longitudinal data, we propose four specific aims: Aim 1 will compare correlations between immunometabolic markers in cachexic and non-cachexic patients; Aim 2 will assess associations between plasma metabolomics, DNA methylation, and weight loss; Aim 3 will develop an integrated immunometabolic network map linking biomarkers to cachexia symptoms; and Aim 4 will evaluate associations between biomarkers and survival outcomes. This research is highly feasible due to the availability of an established cohort with extensive pretreatment omics data and longitudinal patient outcomes. By uncovering the key mechanisms underlying cachexia and their systemic interplay, this study will provide crucial insights that are currently missing in human cachexia research. The findings could lead to targeted biomarkers and interventions, ultimately improving early detection, treatment, and quality of life for cancer patients. The significance of this research lies in its potential to revolutionize our understanding of cachexia as a systemic disorder and to provide a path toward effective interventions for this devastating condition.