| Accession |
PRJCA016328 |
| Title |
Metabolic classification indicates the chemosensitivity of pancreatic ductal adenocarcinoma and suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target |
| Relevance |
Medical |
| Data types |
Whole genome sequencing
Epigenomics
Transcriptome or Gene expression
Metabolome
|
| Organisms |
Homo sapiens
|
| Description |
Chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) is still an inevitable challenge in the clinic. Metabolic reprogramming is known as an emerging mechanism of therapy resistance. However, the metabolic signatures of PDAC are largely unknown. Thus, systematically characterizing the metabolic signatures of PDAC and developing pharmacological strategies targeting the tumor metabolism pathway using clinical-grade inhibitors are imperative. Here, we characterized the metabolomic profile of PDAC organoids, and classified PDAC organoids as glucomet-PDAC (high glucose metabolism levels) or lipomet-PDAC (high lipid metabolism levels). Glucomet-PDAC organoids were more resistant to chemotherapy than lipomet-PDAC organoids, and patients with glucomet-PDAC signatures had a worse prognosis. Integrated analyses revealed that the GLUT1/ALDOB/G6PD axis induced chemoresistance by remodeling glucose metabolism in glucomet-PDAC organoids. Increased glycolytic flux, G6PD activity and pyrimidine biosynthesis were identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or increasing ALDOB expression. Pharmacological inhibition of GLUT1 or G6PD enhanced the chemotherapy response of glucomet-PDAC models. We also identified two clinical grade inhibitors of G6PD (MLN8054 and Alisertib) as a potential therapeutic agent for chemoresistant PDAC patients. Our findings uncovered potential metabolic heterogeneity related to differences in chemotherapy sensitivity in PDAC and developed a promising pharmacological strategy involving the combination of GLUT1/ALDOB/G6PD axis inhibitors and chemotherapy for patients with chemo-resistant glucomet-PDAC. |
| Sample scope |
Multiisolate |
| Release date |
2023-04-17 |
| Publication |
| PubMed ID |
Article title |
Journal name |
DOI |
Year |
| 37597521
|
Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer
|
Cell Reports Medicine
|
10.1016/j.xcrm.2023.101162
|
2023
|
|
|
| Grants |
| Agency |
program |
Grant ID |
Grant title |
| National Key Research and Development Program of China
|
|
2020YFA0509000
|
|
| Chinese Academy of Sciences (CAS)
|
|
ZDBS-LY-SM015
|
|
| National Natural Science Foundation of China (NSFC)
|
|
32125013
|
|
|
|
| Submitter |
dong
gao (dong.gao@sibcb.ac.cn)
|
| Organization |
Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences |
| Submission date |
2023-04-17 |
