Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors

  • Sci Signal. 2026 Mar 3;19(927):eadz6443. doi: 10.1126/scisignal.adz6443.
Kathryn Buscher  1 ,  Kelsey Temprine  2 ,  Christopher Mays  1 ,  Noora Aabed  1 ,  Samuel A Kerk  1  3 ,  Hannah N Bell  1 ,  Joseph A Nieto Carrion  1 ,  Harrison S Greenbaum  1  4  5 ,  Zheng Hong Lee  1  6 ,  Varun Ponnusamy  1 ,  Sadeesh K Ramakrishnan  7 ,  Costas A Lyssiotis  1  8  9 ,  Xiang Xue  10 ,  Yatrik M Shah  1  8  9
Affiliations
  • 1. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 2. Department of Biomedical Sciences, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI 49007, USA.
  • 3. Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 4. Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5. Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA.
  • 6. Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 7. Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 8. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109, USA.
  • 9. Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • 10. Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA.
PMID: 41774818 DOI: 10.1126/scisignal.adz6443
Abstract

The JAK-STAT3 signaling pathway is a key driver of colorectal Cancer (CRC) progression. STAT3 is a transcription factor that is canonically activated by cytokines, such as IL-6, in a transient manner because of negative feedback mechanisms. However, STAT3 is aberrantly and persistently activated in CRC, promoting tumor cell proliferation and survival. Here, we demonstrated that glucose sustained STAT3 activation independently of cytokine availability. We manipulated glucose metabolism, which showed that both glucose and its downstream metabolite GlcNAc were essential to maintain STAT3 activation. Moreover, cells with high basal STAT3 activity produced proteins that were glycosylated in a glucose-dependent manner and that activated STAT3 in neighboring cells through paracrine signaling. Proteomic analysis identified multiple candidate proteins involved in this process; however, no single protein was sufficient to fully activate STAT3, suggesting that this activation process requires several glycosylated proteins. In a syngeneic mouse model of CRC, inhibition of glycolysis reduced STAT3 activation in tumors, and genetic deletion of STAT3 substantially decreased tumor growth. Together, these findings show how glucose metabolism supports sustained STAT3 activation in CRC, highlighting a potential metabolic vulnerability for therapeutic targeting.

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