129 Colorectal cancer is the third most common cancer in the US. Although screening has led to a decrease in incidence over the past 20 years, early-onset colorectal cancer has been rising. Despite advances in surgery and therapies, patients with metastatic colorectal cancer continue to have poor outcomes, highlighting the need for novel treatments. In patients with colorectal cancer, the protein STAT3 is continuously activated, leading to tumour growth. In a new study published in Science Signaling, University of Michigan researchers have shown that glucose levels sustain the increased STAT3 activation in colorectal cancer cells. Their findings suggest that targeting glucose metabolism could inhibit STAT3, leading to novel therapeutic strategies. The researchers used colorectal cancer cell lines to identify what factors cause increased STAT3 activation. They found that normal blood glucose levels are enough to increase activation, while depriving cells of glucose decreased it. “It has been known for a while that glucose and other sugars have a pro-tumourigenic role, where they promote cancer development,” said Yatrik Shah, professor of molecular and integrative physiology and member of the Rogel Cancer Center. “We have shown that the activation of the STAT3 signaling pathway is one reason why.” The researchers observed similar results in pancreatic, liver, and cervical cell lines. They showed that the effect of glucose on STAT3 is controlled by glycosylated proteins, which are formed by adding sugar groups to specific proteins. Although they do not know the identity of these molecules, the researchers showed that the glycosylated proteins are secreted from colorectal cells. In addition to activating STAT3 inside the cells that produce them, the molecules also enter neighbouring cells to do the same. The researchers are trying to identify the glycosylated proteins that are secreted and understand which molecules need to be targeted. “STAT3 signaling is important in a wide variety of diseases, including fatty liver disease and inflammatory bowel disease and we believe that our results will have far-reaching roles beyond cancer,” said Kathryn Buscher, a graduate student in the Shah lab and first author of the study.