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Molecular Diagnostics

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

British Journal of Cancer volume 128, pages 844–856 (2023)Cite this article

Subjects

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.

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Fig. 1: Hyperglycaemia induces YAP / TAZ overexpression and trigger the glycolytic phenotype in the metabolic pathway in PDAC cells.
Fig. 2: Hyperglycaemia promotes EMT by YAP/TAZ overexpression in PDAC cells.
Fig. 3: Hyperglycaemia enhances chemoresistance by upregulating ABCB1 expression via YAP/TAZ overexpression in PDAC cells.
Fig. 4: Hyperglycaemia triggers an alteration of molecular subtype in cancer cells via YAP/TAZ- Hedgehog signalling axis.
Fig. 5: Hyperglycaemia promoted malignant behaviour of PDAC via YAP/TAZ in vivo.
Fig. 6: Hyperglycaemia promotes collagen deposition by activating cancer-associated fibroblasts via YAP/TAZ overexpression.

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Data availability

All presented data are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr. Hiromitsu Hayashi, Dr. Norio Uemura and Dr. Kazuki Matsumura for helping with the study; Ms. Ogata, Ms. Yasuda and Ms. Taniguchi for their excellent technical assistance; Dr. Feng Wei, Dr. Chuan Lan and Dr. Xiyu Wu for giving me good advices; Shigeki Nakagawa, Kosuke Mima, Katsunori Imai, Yo-ichi Yamashita and Prof. Hideo Baba for assistance with revision of the paper. Data sharing requests will be considered by the management group upon written request to the corresponding author.

Funding

This work was supported by a Grant-in-Aid for Scientists (C); the Ministry of Education, Culture, Sports, Science, and Technology of Japan, No. 19K09177 (to HH); the Takeda Science Foundation, Japan (to HH); Japanese Foundation for Multidisciplinary Treatment of Cancer, Japan (to HH) and JST SPRING, Grant Number JPMJSP2127 (to ZL).

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

    Zhao Liu, Hiromitsu Hayashi, Kazuki Matsumura, Yoko Ogata, Hiroki Sato, Yuta Shiraishi, Norio Uemura, Tatsunori Miyata, Takaaki Higashi, Shigeki Nakagawa, Kosuke Mima, Katsunori Imai & Hideo Baba

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Contributions

Conceived and designed the experiments: ZL and HH. Performed the experiments: ZL, NU, KM and YO. Analysed the data: ZL and HH. Wrote the manuscript: HH and ZL. Collected clinical samples: ZL, NU, KM, HS, YS, TM and TH. Organised the paper and approved the final version to be published: HH, SN, KM, KI and HB.

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Correspondence to Hideo Baba.

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The study was approved by the Medical Ethics Committee of Kumamoto University (Project No. 1291), and written informed consent was obtained from all human subjects.

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Liu, Z., Hayashi, H., Matsumura, K. et al. 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 128, 844–856 (2023). https://doi.org/10.1038/s41416-022-02106-9

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