Unveiling the systemic nature of pancreatic cancer cachexia: multi-organ interactions underpin a deadly syndrome

Pancreatic cancer cachexia is a complex, multifactorial syndrome characterized by progressive weight loss, skeletal muscle and fat wasting, and systemic inflammation. Occurring in over 60% of pancreatic cancer patients, cachexia significantly reduces physical function, impairs treatment tolerance, and shortens overall survival. Unlike starvation, cachexia cannot be fully reversed by nutritional support alone. A new review article published in hLife provides a detailed and up-to-date understanding of pancreatic cancer cachexia as a systemic disease that is driven by tumor-host interactions across multiple organs.

Researchers from the Peking Union Medical College Hospital and Harvard T.H. Chan School of Public Health summarize decades of work repositioning cachexia from a localized metabolic disturbance to a cancer-driven, multi-organ pathology. The review categorizes cachexia-inducing factors into inflammatory cytokines (e.g., TNF-α, IL-6), TGF-β superfamily members (e.g., activin A, myostatin, GDF15), catabolic mediators (e.g., proteolysis-inducing factor and lipid mobilizing factor), and extracellular vesicles (EVs) released by tumors. These mediators cause not only muscle atrophy and fat loss, but also appetite suppression, gut dysfunction, neuroendocrine disruption, and cardiac damage.

Pancreatic tumors activate distinct catabolic signaling cascades that disrupt the balance between protein synthesis and degradation in muscle tissue. In particular, cancer-associated stress leads to the overactivation of the ubiquitin-proteasome pathway (UPP), where key E3 ubiquitin ligases, such as MAFbx (atrogin-1) and MuRF1, are upregulated, resulting in accelerated protein degradation and muscle atrophy. Simultaneously, adipose tissue loss is primarily attributed to enhanced lipolysis mediated by two key lipases: adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL). These enzymes break down triglycerides into free fatty acids and glycerol, fueling the systemic energy demands of the tumor and contributing to whole-body wasting. The increased activity of these lipases is often potentiated by inflammatory signals and tumor-derived factors, which override the normal anabolic and energy storage functions of adipose tissue. Notably, the authors highlight emerging evidence showing that organs such as the skeletal muscle, adipose tissue, liver, and brain engage in reciprocal crosstalk with tumors, amplifying metabolic imbalance and organ dysfunction. These pathophysiological changes are majorly mediated by cachexia-inducing factors delivering molecular signals that exacerbate cachexia through both local and systemic routes. These findings suggest that cachexia should be addressed as a systemic disease rather than an isolated consequence of cancer.

In addition to providing mechanistic insights, the review discusses existing experimental models, such as genetically engineered mouse models and xenograft models, that enable researchers to dissect the pathophysiology of cachexia. The authors also describe how promising experimental models, such as organoids and organ chips, can advance the study of this systemic disease.

Proposed therapeutic strategies include blocking key signaling pathways such as IL-6/STAT3, TGF-β/SMAD, and PI3K/Akt/mTOR, neutralization of cachexia-inducing factors such as GDF15, as well as interfering with the release and uptake of tumor EVs. Early interventions that target the systemic inflammatory state or alleviate the metabolic dysregulation may significantly improve patient outcomes.

“This review reframes cachexia not as a symptom but as a cancer-initiating, whole-body syndrome,” said Prof. Wenming Wu, corresponding author of the article. “By identifying the drivers of systemic deterioration, we open the door to more effective diagnostics and interventions.”

The article underscores an urgent need for cross-disciplinary approaches—combining oncology, metabolism, immunology, and neuroscience—to fully understand and combat pancreatic cancer cachexia. These insights have the potential to transform clinical care and improve the lives of patients with this aggressive disease.

About Author: (Briefly outline the corresponding author's academic achievements and research contributions) (One author only)

Wenming Wu is currently Vice President of Peking Union Medical College Hospital (PUMCH) and Director of the PUMCH Macau Medical Center at the Cotai Healthcare Complex. He is a tenured professor at Peking Union Medical College, Chief Physician of the Department of General Surgery at PUMCH, and a doctoral supervisor. Prof. Wu has long been dedicated to basic and translational research in pancreatic tumors, as well as clinical studies in pancreatic surgery. He has published a series of high-impact research papers in top international journals such as Gut, Cell Research, Nature Cancer, and Cancer Letters, and his work has been highly recognized by peers worldwide. Prof. Wu currently serves as Vice President of the Chinese Society of Pancreatology, Deputy Secretary-General of the Surgery Branch of the Chinese Medical Association, and Vice President of the Surgery Branch of the Chinese Medical Doctor Association. He is also Deputy Editor-in-Chief of the Journal of Pancreatology.