Tumor-derived SAA1-TLR4 signaling drives tumor-to-muscle communication in pancreatic cancer cachexia
Cancer cachexia limits treatment tolerance and survival in pancreatic ductal adenocarcinoma (PDAC), yet the tumor-derived signals driving tissue dysfunction remain poorly understood. Here, we identify serum amyloid A1 (SAA1) as a mediator of tumor-to-host communication acting through Toll-like receptor 4 (TLR4). Tumor-derived SAA1 was elevated in human PDAC and in a mouse PDAC model and disrupted…
Pancreatic ductal adenocarcinoma (PDAC) is associated with cancer cachexia, which reduces treatment tolerance and survival. However, the signals from tumors that cause this tissue dysfunction are not well understood. Researchers have now identified serum amyloid A1 (SAA1) as a key mediator of tumor-to-host communication through Toll-like receptor 4 (TLR4). Elevated levels of SAA1 are found in human PDAC and a mouse PDAC model. This molecule disrupts the homeostasis of both muscle cells and myofibers.
By genetically reducing SAA1 in the tumor, the researchers were able to uncouple tumor progression from host wasting. This intervention preserved muscle mass and function, and extended survival without affecting the growth of the primary tumor. SAA1-TLR4 signaling is responsible for remodeling the skeletal muscle microenvironment. After cachexia sets in, inhibiting TLR4 restores muscle mass, function, and the number of muscle stem cells (MuSC), and prolongs survival regardless of the tumor's growth.
The researchers found that SAA1-TLR4 signaling is conserved in human skeletal muscle. This discovery presents a promising therapeutic target for targeting host deterioration independently of tumor progression.
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