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  3. Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer

Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer

  • Cell Rep Med. 2023 Aug 10;101162. doi: 10.1016/j.xcrm.2023.101162.
Yunguang Li 1,  Shijie Tang 1,  Xiaohan Shi 2,  Jingwen Lv 3,  Xueyuan Wu 1,  Yehan Zhang 1,  Huan Wang 2,  Juan He 1,  Yiqin Zhu 4,  Yi Ju 4,  Yajuan Zhang 1,  Shiwei Guo 2,  Weiwei Yang 5,  Huiyong Yin 6,  Luonan Chen 7,  Dong Gao 8,  Gang Jin 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
  • 3 CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Innovation Center for Intervention of Chronic Disease and Promotion of Health, Chinese Academy of Sciences (CAS), Shanghai 200031, China.
  • 4 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
  • 5 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: weiweiyang@sibcb.ac.cn.
  • 6 CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Innovation Center for Intervention of Chronic Disease and Promotion of Health, Chinese Academy of Sciences (CAS), Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China. Electronic address: hyyin@sibs.ac.cn.
  • 7 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: lnchen@sibcb.ac.cn.
  • 8 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: dong.gao@sibcb.ac.cn.
  • 9 Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China. Electronic address: jingang@smmu.edu.cn.
PMID: 37597521 DOI: 10.1016/j.xcrm.2023.101162
Abstract

Metabolic reprogramming is known as an emerging mechanism of chemotherapy resistance, but the metabolic signatures of pancreatic ductal adenocarcinomas (PDACs) remain unclear. Here, we characterize the metabolomic profile of PDAC organoids and classify them into glucomet-PDAC (high glucose metabolism levels) and lipomet-PDAC (high lipid metabolism levels). Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression. Pharmacological inhibition of GLUT1 or G6PD enhances the chemotherapy response of glucomet-PDAC. Our findings uncover potential metabolic heterogeneity related to differences in chemotherapy sensitivity in PDAC and develop a promising pharmacological strategy for patients with chemotherapy-resistant glucomet-PDAC through the combination of chemotherapy and GLUT1/ALDOB/G6PD axis inhibitors.

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