Scientists reveal metabolic typing of pancreatic cancer and the mechanism of chemotherapy resistance

On August 18, the international academic journal Cell Reports Medicine published online the collaborative research results of Gao Dong Research Group, Chen Luonan Research Group, Yang Weiwei Research Group of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Jin Gang Research Group of the First Affiliated Hospital of Naval Military Medical University (Shanghai Changhai Hospital), and Yin Huiyong Research Group of Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences: Metabolic classification suggests GLUT1/ ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer。 This study systematically reveals the metabolomic characteristics of pancreatic ductal adenocarcinoma (PDAC), and proposes chemotherapy sensitivity mechanisms and potential therapeutic targets of different metabolic subtypes by integrating metabolome, genome-wide, transcriptome and drug sensitivity data and other multi-omics data.

With a 5-year survival rate of 11%, PDAC is the most malignant solid tumor. Chemotherapy can significantly prolong survival in patients with PDAC, but chemotherapy response rates in patients with PDAC remain low due to complex and unclear resistance mechanisms. Genomic and transcriptome-based typing has failed to guide chemotherapy sensitivity or clinical treatment of PDAC, which is still treated as a single type of tumor. Tumor metabolic reprogramming is thought to be an emerging therapeutic resistance mechanism, however the abundance of mesenchymal cells in PDAC makes it difficult to capture tumor-specific metabolic information. Patient-derived tumor organoids have been shown to outperform traditional cell lines in reproducing the characteristics of primary tumors as a novel research model. It is of great scientific value and clinical application to use organoid models to deeply explore the metabolomic characteristics of pancreatic cancer and integrate and analyze multi-omics data to reveal the differences in pancreatic cancer metabolism and potential drug targets.

The research team systematically collected information on metabolomics, whole genomes, transcriptomics, chromatin openness and drug sensitivity using 28 pancreatic cancer organoids as models. Metabolomics were used to classify PDAC and identify two metabolic subtypes, which were enriched for glycan metabolism (Glucomet-PDAC) and lipid metabolism (Lipomet-PDAC). Compared to Lipomet-PDAC, Glucomet-PDAC is more resistant to chemotherapy and patients with Glucomet-PDAC features have a worse prognosis. Further integration of multiomics found that the GLUT1/ALDOB/G6PD metabolic axis plays an important role in the metabolic reprogramming of Glucomet-PDAC. First, in Glucomet-PDAC, Glut1 is highly expressed, transporting more glucose into tumor cells. Secondly, the decrease in ALDOB expression released the activity of G6PD and increased the metabolic flux of the oxidized pentose phosphate pathway. The increase in the metabolic flux of the oxidized pentose phosphate pathway synthesized more raw materials involved in DNA synthesis in Glucomet-PDAC, inducing its resistance to chemotherapy drugs. Knocking down GLUT1, overexpressing ALDOB, or knocking down G6PD in Glucomet-PDAC can all lead to increased cell sensitivity to chemotherapy drugs. Similarly, inhibitors of GLUT1 and G6PD increase the sensitivity of PDAC to chemotherapy drugs in vitro and in vivo. Finally, through virtual screening and in vitro and in vitro verification, it was found that Aurora’s two clinical inhibitors, MLN8054 and Alisertib, can effectively inhibit the activity of G6PD and increase the sensitivity of chemotherapy drugs. The study revealed potential metabolic heterogeneity associated with chemotherapy sensitivity to PDAC and developed a promising pharmacological strategy for chemotherapy-resistant glucomet-PDAC patients through a combination of chemotherapy and GLUT1/ALDOB/G6PD axis inhibitors.

Prof. Gao Dong, Prof. Luonan Chen, Prof. Weiwei Yang of the Center of Excellence for Molecular Cells, Prof. Huiyong Yin from the Institute of Nutrition and Health, and Professor Jin Gang from the Department of Hepatobiliary, Pancreatic, and Spleen Surgery of Shanghai Changhai Hospital are co-corresponding authors of the paper. Yunguang Li, postdoctoral fellow Shijie Tang, Xueyuan Wu, Yehan Zhang, Xiaohan Shi, Ph.D. Shi Xiaohan, Department of Hepatobiliary, Pancreatic and Spleen Surgery, Shanghai Changhai Hospital, and Jingwen Lv, Institute of Nutrition and Health, are co-first authors of the paper. The research work was supported by the National Key R&D Program, the National Natural Science Foundation of China, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Commission. The research work was supported by the Molecular Cell Center of Excellence Cell Analysis Technology Platform, Chemical Biology Technology Platform and Animal Experiment Technology Platform. (Source: Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences)

Related paper information:

Map of pancreatic cancer metabolic typing and its reprogramming-induced resistance patterns

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