A research team has conducted a study exploring the role of the mannose pathway in regulating cell fate decisions in low glucose environments. Their work may hold potential for novel therapeutic strategies in cancer treatments. The research is published in the Journal of Biological Chemistry on January 28, 2026.
Scientists know that mammalian cells, those basic functional building blocks of all mammals including humans, use diverse metabolic pathways to regulate cell fates when they are deprived of glucose. This glucose deprivation occurs in the tumor microenvironment because the cancer cells rapidly and inefficiently consume the glucose for energy and biosynthesis. The glucose supply cannot keep up with the cancer cells’ rapid consumption.
Cancer cells survive in this glucose-deprived environment through a wide range of adaptive responses. These responses include the activation of survival signals and the optimization of metabolic activity. Scientists also know that glucose deprivation lowers the metabolic activity of the mannose pathway. The mannose pathway is a metabolic process where the sugar mannose is synthesized and incorporated into structural components such as N -glycans. Although scientists have long recognized these responses, its cellular role was unknown, mostly because of metabolic complications caused by the glucose deprivation.
“How cancer cells survive in a glucose-poor tumor microenvironment remains incompletely understood,” says Professor Yoichiro Harada, from the Institute for Glyco-core Research (iGCORE), Nagoya University. Gaining an understanding of the molecular responses against glucose deprivation is crucial for the development of effective cancer treatments.
The mannose pathway is interconnected with the metabolic process called glycolysis. The team genetically engineered cells to separate the mannose pathway from glycolysis. This allowed them to have precise control of the mannose pathway activity by adjusting the mannose supply levels instead of changing the glucose supply.
They found that a moderate decrease in the mannose pathway activity led to impaired N -glycan biosynthesis and activated pro-survival signals in the endoplasmic reticulum. They further decreased the mannose pathway activity to minimal levels that did not compromise cell survival. However, these decreases in mannose pathway activity depleted the luminal protective glycocalyx of lysosomes. The lysosome is a tiny sac in a cell that works like the cell’s “digestive system” that breaks down waste materials and converts them into components the cell can reuse. Little protective glycocalyx in the lysosome impairs lysosomal integrity and increases the risk of cell death.
Their results showed that the low metabolic flow of glucose into the mannose pathway initiates changes in the cells. These changes include the activated stress response in the endoplasmic reticulum, the networks of membranes that is the cell’s transport system, and the depleted glycocalyx in the lysosomes. These changes occur, in part, because of defects in the cellular process called N -glycosylation. The defects impact cell fate decisions. The team discovered that “cancer cells take advantage of reduced glucose utilization in N -glycan biosynthesis to activate pro-survival signaling,” said Harada.
Looking ahead, the team notes that further studies are necessary to explain the mechanisms that determine cell fates during glucose deprivation. “The next step is to explore ways to inhibit these pro-survival signals, which may provide new insights into development of therapeutic strategies for cancer,” says Harada.
The research team includes Ziwei Wang from Osaka International Cancer Institute and The University of Osaka; Yasuhide Miyamoto, Miki Tanaka-Okamoto, Yu Mizote, Hideaki Tahara and Naoyuki Taniguchi from Osaka International Cancer Institute; Takehiro Suzuki and Naoshi Dohmae from RIKEN Center for Sustainable Resource Science; Yoichiro Harada from Osaka International Cancer Institute, The University of Osaka, and Nagoya University.
The research is funded by Takeda Science Foundation, JSPS KAKENHI, the Mizutani Foundation for Glycosciences, and Daiko Foundation.
Journal of Biological Chemistry
Experimental study
Cells
Mannose metabolic pathway senses glucose supply and regulates cell fate decisions
28-Jan-2026