Glucose drives STAT3 activation in colorectal cancer cells, leading to tumor growth

Colorectal cancer is the third most common cancer in the United States.

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 tumor 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 the 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-tumorigenic 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 don’t 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 neighboring 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.

Additional authors: Kelsey Temprine, Christopher Mays, Noora Aabed, Samuel Kerk, Hannah N. Bell, Joseph A. Nieto Carrion, Harrison Greenbaum, Zheng Hong Lee, Varun Ponnusamy, Sadeesh K. Ramakrishnan, Costas A. Lyssiotis and Xiang Xue.

Funding/disclosures: Shah was supported by NIH grants #R01CA148828, #R01CA245546 and #R01DK095201; the GI SPORE Molecular Pathology and BioSample Core #P50CA130810; the Center for Gastrointestinal Research #DK034933 and the Department of Defense #CA171086. Both Shah and Lyssiotis were supported by the University of Michigan Comprehensive Cancer Center Core grant #P30CA046592. Lyssiotis was supported by NIH/NCI grants R37CA237421, R01CA248160 and R01CA244931. Xue was supported by NIH grant 1R01ES035780-01A1. Carrion was supported by the University of Michigan Rackham Merit Fellowship.

Tech transfer(s)/Conflict(s) of interest: Lyssiotis has served as a consultant for Astellas Pharmaceuticals, Odyssey Therapeutics, Third Rock Ventures and T-Knife Therapeutics. He is also an inventor on patents related to KRAS-regulated metabolic pathways, redox control mechanisms in pancreatic cancer, and therapeutic targeting of the GOT1-ME1 pathway (U.S. Patent No. 2015126580-A1, 2015; U.S. Patent No. 20190136238, 2019; and International Patent No. WO2013177426-A2, 2015).

Paper cited: “Glucose Metabolism Sustains Aberrant STAT3 Signaling in Colorectal Cancer via Glycosylated Local Signaling Factors,” Science Signaling. DOI: 10.1126/scisignal.adz6443.

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