Cell Paper Identifies Subclusters Driving Cancer-Induced Cachexia

OKLAHOMA CITY – Research published today in Cell identifies three small subclusters of cells driving pancreatic cancer-induced cachexia, a muscle-wasting and fat-loss condition that makes patients less tolerant of cancer treatment. The study, led by the University of Oklahoma, holds significant promise for the development of therapeutics to target these subclusters.

Together, the three subclusters form a triangular regulatory network, working in a feed-forward loop to drive the initiation and progression of cachexia.

“These are the players that are driving cachexia in pancreatic cancer patients. We successfully identified and isolated these small cell clusters from each cell type in the tumor microenvironment. Our next steps are to develop specific strategies to target these three molecules,” said lead author Min Li, Ph.D., OU College of Medicine professor of medicine and associate director for global oncology for OU Health Stephenson Cancer Center.

Li and his team found that the cell subclusters form what is called a molecular niche. Using cutting-edge technologies like single-cell sequencing and spatial transcriptomics, they discovered that the subclusters are physically adjacent to one another, forming a microenvironment that is conducive to cachexia. The subclusters are SEMA4A+ tumor cells, AQP9+ macrophages and LOXL2+ cancer-associated fibroblasts.

“The presence of these three cell subclusters may help identify patients who are likely to progress to pre-cachexia and cachexia,” Li said.

In addition to having therapeutic potential, the findings underscore the importance of diagnosing and treating cachexia early. Li said the subclusters form before muscle and fat loss occur. Addressing cachexia early could ultimately help the patient be more tolerant of pancreatic cancer treatment.

Any eventual treatment for cachexia would also need to be given in combination with pancreatic cancer treatment, whether chemotherapy or a targeted therapy, Li said.

“We need to slow down tumor growth at the same time we’re slowing the progression of cachexia,” he said. “Otherwise, if we’re only lowering the burden of the tumor, patients quickly become cachexic and lose muscle strength and appetite, making them less able to withstand treatment.”

Robert S. Mannel, M.D., director of the OU Health Stephenson Cancer Center and professor in the OU College of Medicine, said the findings represent an important advancement for patients with pancreatic cancer.

“Cachexia has a profound impact on patients’ quality of life and their ability to tolerate cancer treatment,” Mannel said. “This discovery gives us new insight into what drives cachexia and opens the door to detecting and treating it earlier.”

Ian F. Dunn, M.D., executive dean of the OU College of Medicine and chief physician executive for OU Health, said the study demonstrates how fundamental scientific discovery can lay the groundwork for advances in patient care.

“Dr. Min Li and his colleagues’ work advances our understanding of pancreatic cancer cachexia and provides a foundation for new therapeutic strategies to address this debilitating condition,” Dunn said. “Their findings illustrate the potential of fundamental discovery to inform clinical advances and bring hope to patients and families. The publication in Cell reflects the significance of this work and the caliber of discovery taking place at the OU College of Medicine on the Harold Hamm Health Campus.”

Over the past several years, Li’s research has developed into a more sophisticated understanding of cachexia. In a 2024 paper in Cancer Cell, he discovered that crosstalk between pancreatic cancer cells and macrophages (a type of immune cell) is the first step toward the onset of cachexia. In a paper earlier this year, also published in Cancer Cell, he set forth the triangle regulation theory in which cancer cells recruit and activate macrophages which, in turn, enlist the involvement of the central nervous system.

Pancreatic cancer is an especially deadly type of cancer, with a five-year survival rate below 13% across all stages. Over 80% of patients with pancreatic cancer will develop cachexia, and nutritional support does not reverse the symptoms.

“There are no good treatments for cachexia,” Li said. “That’s why this paper is so exciting. We believe the findings show great clinical relevance and promise for early detection and therapeutic intervention of cachexia.”

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About the project

“Spatial Evolution of a Cachexia-Promoting Microenvironment in Pancreatic Cancer” can be found at https://doi.org/10.1016/j.cell.2026.09.012. The research was supported by the OU College of Medicine, the college’s Department of Medicine, and the OU Health Stephenson Cancer Center on the OU Harold Hamm Health Campus. Stephenson Cancer Center is supported in part by Oklahoma’s Tobacco Settlement Endowment Trust (TSET).

About the University of Oklahoma

Founded in 1890, the University of Oklahoma is a public research university with campuses in Norman, Oklahoma City and Tulsa. As the state’s flagship university, OU serves the educational, cultural, economic and healthcare needs of the state, region and nation. In Oklahoma City, the Harold Hamm Health Campus is one of the nation’s few academic health centers with seven health profession colleges located on the same campus. The Harold Hamm Health Campus serves approximately 4,000 students in more than 70 undergraduate and graduate degree programs spanning Oklahoma City and Tulsa and is the leading research institution in Oklahoma. For more information about the Harold Hamm Health Campus, visit www.ouhsc.edu.