We are very pleased to share the chemotherapy-resistant pancreatic cancer study published in Cell Reports Medicine Journal. The authors of "Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer" utilized our proprietary the widely-targeted metabolomics and lipidomics detection and reported 1000+ metabolites. The aim of this study was to explore how potential metabolic heterogeneity related to differences in chemotherapy sensitivity in PDAC and to develop a promising pharmacological strategy for patients with chemotherapy-resistant glucomet-PDAC through the combination of chemotherapy and GLUT1/ALDOB/G6PD axis inhibitors.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and has a 5-year survival rate of 11%. Chemotherapy could significantly prolong the survival of patients with PDAC, but the chemotherapy response rate of patients with PDAC remains low due to complex and unclear drug-resistance mechanisms. Metabolic reprogramming is recognized as an emerging mechanism of therapy resistance and presents opportunities for cancer treatment. Few studies, however, have examined the metabolic dysregulation and heterogeneity of PDAC because of the presence of abundant stromal cells, making capturing precise tumor-specific metabolite information difficult.
This group have established a large PDAC organoid biobank and characterized these organoids by multiomics integration analysis. They characterized the metabolic profiles of 28 patient-derived PDAC organoids via a widely targeted metabolomics assay, and investigated whether the metabolic subtypes were associated with clinical outcomes. Moreover, they presented a potential pharmacological strategy that involves targeting the GLUT1/ALDOB/G6PD axis to enhance the therapeutic sensitivity of glucomet-PDAC.
The widely targeted metabolomics assay in 28 patient-derived PDAC organoids was performed, and the authors identified two optimal metabolic subtypes according to targeted metabolomics. Class 2 organoids were characterized by marked enrichment of carbohydrate metabolism, energy metabolism, and nucleotide metabolism, indicating increased glucose metabolism. Metabolic flux in glycolysis and the tricarboxylic acid (TCA) cycle was significantly increased in class 2. The oxidative pentose phosphate pathway (PPP) metabolites G6P, 6PG, and R5P, but not the nonoxidative PPP metabolites S7P and E4P, were highly enriched in class 2 organoids, suggesting glucose metabolic reprogramming in class 2. Thus, the authors termed class 2 organoids as glucomet-PDAC. Class 1 was characterized by relatively enriched lipid metabolism. Finally, these metabolic profiles classified PDAC into lipomet-PDAC (high lipid metabolism levels) and glucomet-PDAC (high glucose metabolism levels) with elevated lipid and glucose metabolism, respectively.
An essential role for the GLUT1/ALDOB/G6PD axis in regulating metabolic reprogramming enhances glucose entry into glycolysis, the TCA cycle, and the oxidative PPP in glucomet-PDAC. Increased flux of glycolysis and the PPP leads to an increase in nucleoside biosynthesis, including the synthesis of pyrimidine and purine nucleosides, which serve as important inducers of drug resistance. Widely targeted metabolomics analysis indicated that pyrimidine and purine pathway-related metabolites were enriched in glucomet-PDAC. Increased levels of nucleosides and nucleoside derivatives could be detected in glucomet-PDAC. Activated G6PD and increased flux of oxidative PPP provide R5P for nucleotide biosynthesis. GLUT1 knockdown, ALDOB overexpression, or G6PD knockdown distinctly increased the sensitivity to four chemotherapeutic drugs that work by inhibiting DNA synthesis in glucomet-PDAC organoids. The addition of exogenous pyrimidine nucleosides and R5P effectively rescued the increase in drug sensitivity induced by GLUT1 knockdown, ALDOB overexpression, or G6PD knockdown in glucomet-PDAC cells.
In conclusion, 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.
The findings underscore the importance of distinguishing between different subtypes of pancreatic ductal adenocarcinoma (PDAC) based on their metabolic characteristics. The integration of multiple analyses provides a comprehensive picture of the metabolic alterations associated with chemotherapy resistance. Importantly, the suggestion that reversing these phenotypes through the modulation of GLUT1 and ALDOB expression or the use of pharmacological inhibitors could enhance chemotherapy response is a promising avenue for further investigation and potential clinical intervention.The findings have the potential to improve patient outcomes by guiding the development of more effective treatment strategies for this challenging cancer subtype.
At Metware lab in Boston we offer the following metabolomics analysis services to support your cancer research:
Quantitative Lipidomics (over 4000 lipids on the panel)
Targeted Bile Acid Assay (65 bile acids)
Energy Metabolism (targeted assay with 68 metabolites)