2. Academic Validation
  3. Glucose Metabolism Sustains Aberrant STAT3 Signaling in Colorectal Cancer via Glycosylated Paracrine Factors

Glucose Metabolism Sustains Aberrant STAT3 Signaling in Colorectal Cancer via Glycosylated Paracrine Factors

  • bioRxiv. 2025 Jul 26:2025.07.22.666143. doi: 10.1101/2025.07.22.666143.
Kathryn Buscher 1,  Kelsey Temprine 2,  Christopher Mays 1,  Noora Aabed 1,  Samuel Kerk 1 3,  Hannah N Bell 1,  Joseph A Nieto Carrion 1,  Harrison Greenbaum 1 4 5,  Varun Ponnusamy 1,  Sadeesh K Ramakrishnan 6,  Costas A Lyssiotis 1 7 8,  Xiang Xue 9,  Yatrik M Shah 1 7 8
Affiliations

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 Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 7 Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109, USA.
  • 8 Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • 9 Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA.
PMID: 40777356 DOI: 10.1101/2025.07.22.666143
Abstract

The JAK-STAT3 signaling pathway is a key driver of colorectal Cancer (CRC) progression. While STAT3 is canonically activated by cytokines such as IL-6, this activation is typically transient due to negative feedback mechanisms. In CRC, however, STAT3 is aberrantly and persistently activated, promoting tumor cell proliferation and survival. Here, we demonstrate that glucose sustains STAT3 activation independent of cytokine availability. By manipulating glucose metabolism, we show that both glucose and its downstream metabolite, GlcNAc, are essential for maintaining STAT3 activation. Moreover, cells with high basal STAT3 activity produce glucose-dependent glycosylated proteins that can activate STAT3 in neighboring cells via paracrine signaling. Proteomic analysis identified multiple candidate proteins involved in this process; however, no single protein was sufficient to fully activate STAT3, suggesting that a combination of glycosylated proteins likely acts synergistically. In vivo, inhibition of glycolysis reduces STAT3 activation in tumors, and genetic deletion of STAT3 in subcutaneous tumor models significantly decreases tumor growth. Together, these findings uncover a novel mechanism by which glucose metabolism supports sustained STAT3 activation in CRC, highlighting a potential metabolic vulnerability for therapeutic targeting.

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