{"doi":"10.1101/2020.05.08.084244","title":"Hypoxia-driven oncometabolite L-2HG maintains “stemness”-differentiation balance and facilitates immune suppression in pancreatic cancer","abstract":"Abstract 2-hydroxyglutarate (2-HG) has gained considerable importance in glioma and blood cancers that have mutations in the IDH1/2 gene. In the current study we show for the first time that pancreatic tumors produce 2HG in the absence of IDH1/2 mutation. Our study shows that hypoxic pancreatic tumors that have activated lactate dehydrogenase (LDH) activity, produce the L-isoform of 2HG. Metabolic mass spectrometric analysis along with chiral derivatization showed that pancreatic cancer cells as well as stromal cells secrete the L-isomeric form of 2-hydroxyglutarate (L-2HG) when exposed to hypoxic environment. Serum analysis of human pancreatic cancer patients also showed similar accumulation of L-2HG. Our results showed that this abnormally accumulated L-2HG regulates self-renewal by increasing expression of genes associated with stemness (Sox-2, CD133) and by decreasing expression of differentiation genes (Pdx-1, HB9, NKX6.1). Further analysis showed that secreted L-2HG mediates cross talk with immune T-cells and hampers their proliferation and migration thereby suppressing the anti-tumor immunity. In vivo targeting of LDH enzyme with inhibitor (GSK2837808A) showed decrease in L-2HG as well as subsequent tumor regression and sensitization to immune-checkpoint therapy. Present study shows for the first time that hypoxia mediated accumulation of L-2HG drives self-renewal in pancreatic cancer by shifting critical balance of gene expression towards stemness and promotes immune suppression by impairing T cell activation in this disease. Additionally, it indicates that targeting LDH can sensitize pancreatic tumors to anti-PD1 therapy by decreasing L-2HG and reverting their immune evasive function.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126612,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":336303,"name":"Nikita Sharma","orcid":"0000-0003-3528-1634","position":1,"is_corresponding":false},{"id":283210,"name":"Brittany Durden","orcid":null,"position":2,"is_corresponding":false},{"id":280517,"name":"Vanessa T. Garrido","orcid":"0000-0002-5014-1608","position":3,"is_corresponding":false},{"id":283209,"name":"Kousik Kesh","orcid":null,"position":4,"is_corresponding":false},{"id":574472,"name":"Dujon Edwards","orcid":"0000-0003-3761-6696","position":5,"is_corresponding":false},{"id":278624,"name":"Dezhen Wang","orcid":"0000-0003-3984-6946","position":6,"is_corresponding":false},{"id":459067,"name":"Ciara Myer","orcid":"0000-0002-2668-8048","position":7,"is_corresponding":false},{"id":575163,"name":"Sanjay K Bhattacharya","orcid":null,"position":8,"is_corresponding":false},{"id":338130,"name":"Ashok K. Saluja","orcid":null,"position":9,"is_corresponding":false},{"id":278626,"name":"Pankaj K. Singh","orcid":"0000-0001-8903-0131","position":10,"is_corresponding":false},{"id":280520,"name":"Sulagna Banerjee","orcid":"0000-0003-2338-1662","position":11,"is_corresponding":false},{"id":280516,"name":"Vineet K. Gupta","orcid":"0000-0002-0307-9485","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T23:15:27.226519Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}