Study on the Pathogenesis and Reversal Strategies of Cancer Cachexia Based on Multi-Omics

Overview

Cancer cachexia is a complex systemic metabolic syndrome with high incidence and mortality rates, significantly impacting the prognosis and survival of cancer patients.Current clinical comprehensive intervention approaches can only provide transient symptom relief and fail to fundamentally block or reverse muscle and fat loss. The core challenge lies in the extreme complexity of this pathological mechanism and the lack of early biomarkers.To overcome the limitations of traditional single-dimensional research approaches, this study proposes a combined analysis method utilizing "multi-omics" (imaging omics, pathological omics, metabolomics, and metagenomics) to construct a panoramic systemic model spanning macroscopic clinical manifestations and microscopic molecular processes. The aim is to comprehensively elucidate the pathogenesis and metabolic pathways of cachexia, thereby precisely identifying potential therapeutic targets capable of reversing this pathological process.

Cancer cachexia is a multifactorial metabolic syndrome characterized by persistent skeletal muscle atrophy, with or without loss of adipose tissue. It differs from conventional malnutrition, for which conventional nutritional support often fails to fully reverse its progression. Cachexia has an extremely high incidence rate in patients with advanced cancer, with an overall prevalence ranging from approximately 50% to 80%. Especially in malignant tumors of the digestive system such as gastric cancer, colorectal cancer, and pancreatic cancer, the incidence of cachexia is higher due to direct involvement of digestive organs by tumors, and the disease prognosis is often more severe. Existing medical evidence indicates that cancer cachexia is closely associated with poor prognosis. Cachexia not only leads to a sharp decline in physical condition and impairment of quality of life, but also significantly reduces tolerance to chemotherapy, radiotherapy, and surgery, while increasing treatment-related toxic side effects. According to statistics, approximately 20% to 30% of cancer-related deaths are not directly attributable to increased tumor burden, but rather to cardiopulmonary failure and metabolic collapse caused by cachexia. Therefore, controlling and reversing cachexia is a critical step in prolonging survival and improving treatment outcomes. At present, clinical treatment of cancer cachexia does not rely on a single approach but rather tends to adopt a "multimodal comprehensive intervention strategy." Specifically, this strategy encompasses enhanced nutritional support therapy (such as providing high-protein, high-calorie enteral/parenteral nutrition formulations), pharmacological interventions (including the use of progestogens to improve appetite and nonsteroidal anti-inflammatory drugs to counter systemic inflammatory responses), and targeted rehabilitation physical training, aiming to maintain functional status through a multidisciplinary approach. However, it must be acknowledged that despite the implementation of the aforementioned comprehensive measures, significant limitations in clinical efficacy remain. In clinical practice, these interventions often only provide temporary symptomatic relief to a limited extent (e.g., short-term improvement in appetite or slowing of weight loss rate), but fail to fundamentally block the "molecular switch" underlying skeletal muscle protein degradation, nor can these interventions effectively reverse already established muscle atrophy and functional decline. The fundamental reason for this dilemma lies in the extreme complexity of the pathogenesis of cachexia. Cachexia is not merely "malnutrition," but rather a "metabolic storm" involving abnormal regulation of multiple organs (muscle, adipose tissue, liver, intestine, etc.) and systems (immune, neuroendocrine, metabolic) throughout the body. Current treatments often only address downstream symptoms without correcting the complex upstream molecular dysregulation. More critically, there is currently an extreme lack of in-depth understanding of the early activation mechanisms of cachexia in clinical practice, and no reliable, high-sensitivity biomarkers (such as specific blood parameters or imaging features) are available. This results in the vast majority of patients being diagnosed with cachexia when the body is already in a severe catabolic state (resistant phase), thereby missing the optimal time window for early intervention and disease reversal. Cancer cachexia is essentially a highly complex systemic metabolic disorder syndrome, with core pathology stemming from extensive and profound abnormal interactions between tumors and the host. These interactions are not confined to the tumor site but also trigger multi-organ functional remodeling, including skeletal muscle and adipose tissue, through inflammatory mediators and metabolic products. In past medical explorations, traditional research models were often confined to single-dimensional observations. This "panoramic view through a tube" approach struggled to reveal the intrinsic connections between macroscopic signs and microscopic molecular mechanisms during the development of cachexia. In recent years, with the advancement of high-throughput biotechnology, "multi-omics" integrated analysis has become a key approach for deciphering such complex diseases. This study aims to overcome traditional limitations by innovatively constructing a panoramic systemic model: the investigators will utilize imaging omics to deeply mine muscle mass and fat infiltration characteristics invisible to the naked eye in CT data, combine pathological omics to observe tumor microenvironment-induced pathological remodeling at the cellular level, simultaneously employ metabolomics to track metabolic dynamic fingerprints in blood and feces, and apply metagenomics to analyze the microecological composition of the "gut-muscle axis." Through this deep integration spanning macro and micro levels, structure and function, the investigators aim to map a comprehensive molecular atlas of cachexia onset and progression, thereby precisely identifying therapeutic targets capable of reversing this pathological process. This multi-level cross-disciplinary research enables the field to transcend the limitations of traditional perspectives, revealing a comprehensive mechanism by which tumors induce muscle and fat loss through altering metabolic environments, reshaping gut microbiota, and inducing histopathological changes-from macroscopic alterations in body composition to microscopic molecular metabolic pathways.