Cell network reveals how pancreatic cancer drives muscle and fat loss
· Medical Xpressby April Wilkerson, University of Oklahoma
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Research published today in Cell identifies three small subclusters of cells that drive pancreatic cancer-induced cachexia, a muscle-wasting and fat-loss condition that makes patients less able to tolerate cancer treatment. The study, led by the University of Oklahoma, could help researchers develop treatments targeting 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.
Three cell groups form a molecular niche
Li and his team found that the cell subclusters form what is called a molecular niche. Using technologies like single-cell sequencing and spatial transcriptomics, they discovered that the subclusters are physically adjacent to one another, forming a microenvironment 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.
Targeting cachexia before muscle loss
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 patients better tolerate 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."
New insight into treatment tolerance
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.
"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."
Earlier discoveries point to an unmet need
Over the past several years, Li's research has yielded 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."
Publication details
Yumeng Hu et al, Spatial evolution of a cachexia-promoting microenvironment in pancreatic cancer, Cell (2026). DOI: 10.1016/j.cell.2026.09.012
Journal information: Cancer Cell , Cell
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