Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer

  • Br J Cancer. 2022 Dec 19. doi: 10.1038/s41416-022-02106-9.
Zhao Liu  1 ,  Hiromitsu Hayashi  1 ,  Kazuki Matsumura  1 ,  Yoko Ogata  1 ,  Hiroki Sato  1 ,  Yuta Shiraishi  1 ,  Norio Uemura  1 ,  Tatsunori Miyata  1 ,  Takaaki Higashi  1 ,  Shigeki Nakagawa  1 ,  Kosuke Mima  1 ,  Katsunori Imai  1 ,  Hideo Baba  2
Affiliations
  • 1. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
  • 2. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. [email protected].
PMID: 36536047 DOI: 10.1038/s41416-022-02106-9
Abstract

Background: Hyperglycaemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in Cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT).

Methods: The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments.

Results: Hyperglycaemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycaemia enhanced chemoresistance by upregulating ABCB1 expression and triggered PDAC switch into pure basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterised by abundant stroma that harbours tumour-promoting properties and chemoresistance. Hyperglycaemia promotes the production of Collagen fibre-related proteins (fibronectin, fibroblast activation protein, COL1A1 and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance and a favourable tumour microenvironment even under hyperglycemic conditions in vitro and in vivo.

Conclusion: Hyperglycaemia induces metabolic reprogramming into glycolytic phenotype and promotes EMT via YAP/TAZ-Hedgehog signalling axis, and YAP/TAZ could be a novel therapeutic target in PDAC.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-138565
    K-975
    99.89%, YAP1/TAZ-TEAD Inhibitor
    target: YAP
    Research Areas: Cancer