General Information
- Project ID
- OEP003254
- Project Name
- Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumor neutrophils with hyperactivated glycolysis in pancreatic tumor microenvironment
- Description
- Objective: Innate immunity plays important roles in pancreatic ductal adenocarcinoma (PDAC), as non-T-cell-enriched tumor. Neutrophils are major players in innate immune system. Here, we aimed to explore the heterogeneity and pro-tumor mechanisms of neutrophils in PDAC. Design: We analyzed single-cell transcriptomes of peripheral blood polymorphonuclear leukocytes (PMNs) and tumor-infiltrating immune cells from five PDAC patients, and performed immunofluorescence/ immunohistochemistry staining, multi-omics analysis, and in vitro experiments to validate the discoveries. Results: Exploration of the heterogeneity of tumor-associated neutrophils (TANs) revealed a terminally-differentiated pro-tumor subpopulation (TAN-1) associated with poor prognosis, an inflammatory subpopulation (TAN-2), a population of transitional stage that have just migrated to tumor microenvironment (TAN-3), and a subpopulation preferentially expressing interferon-stimulated genes (TAN-4). Glycolysis signature was upregulated along neutrophil transition trajectory, and TAN-1 was featured with hyperactivated glycolytic activity. The glycolytic switch of TANs was validated by integrative multi-omics approach of transcriptomics, proteomics and metabolomics analysis. Activation of glycolytic activity by LDHA overexpression in neutrophil-like differentiated HL-60 (dHL-60) cells induced immunosuppression and pro-tumor functions. Mechanistic studies revealed BHLHE40, activated by hypoxia and ER stress, was a key regulator in polarization of neutrophils towards TAN-1 phenotype, and direct transcriptional regulation of BHLHE40 on TAN-1 marker genes was demonstrated by chromatin immunoprecipitation assay. Pro-tumor and immunosuppression functions were observed in dHL-60 cells overexpressing BHLHE40. Importantly, immunohistochemistry analysis of PDAC tissues revealed the unfavorable prognostic value of BHLHE40+ neutrophils. Conclusion: The dynamic properties of TANs revealed by this study will be helpful in advancing PDAC therapy targeting innate immunity.
- Publications
-
Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment
(PMID: 35688610) (DOI: 10.1136/gutjnl-2021-326070)
Project information
- Experiments
- 1
Experiment ID Experiment name Experiment type Create Date OEX016414 PDAC_scRNA-seq Transcriptomic single cell 2022-03-30 - Samples
- 14
Sample ID Sample Name Sample Subject Type Organism Tissue Create Date OES138542 cp_1b Human Homo sapiens pancreas 2022-03-30 OES138543 cp_2b Human Homo sapiens pancreas 2022-03-30 OES138544 hc_1b Human Homo sapiens pancreas 2022-03-30 OES138545 hc_2b Human Homo sapiens pancreas 2022-03-30 OES138546 pdac_1b Human Homo sapiens pancreas 2022-03-30 OES138547 pdac_1t Human Homo sapiens pancreas 2022-03-30 OES138548 pdac_2b Human Homo sapiens pancreas 2022-03-30 OES138549 pdac_2t Human Homo sapiens pancreas 2022-03-30 OES138550 pdac_3b Human Homo sapiens pancreas 2022-03-30 OES138551 pdac_3t Human Homo sapiens pancreas 2022-03-30 OES138552 pdac_4b Human Homo sapiens pancreas 2022-03-30 OES138553 pdac_4t Human Homo sapiens pancreas 2022-03-30 OES138554 pdac_5b Human Homo sapiens pancreas 2022-03-30 OES138555 pdac_5t Human Homo sapiens pancreas 2022-03-30 - Runs
-
14
Run ID Run Name Experiment Sample Data Num Create Date OER252940 cp_1b OEX016414 OES138542 2 2022-04-01 OER252941 cp_2b OEX016414 OES138543 2 2022-04-01 OER252942 hc_1b OEX016414 OES138544 2 2022-04-01 OER252943 hc_2b OEX016414 OES138545 2 2022-04-01 OER252944 pdac_1b OEX016414 OES138546 2 2022-04-01 OER252945 pdac_1t OEX016414 OES138547 2 2022-04-01 OER252946 pdac_2b OEX016414 OES138548 2 2022-04-01 OER252947 pdac_2t OEX016414 OES138549 2 2022-04-01 OER252948 pdac_3b OEX016414 OES138550 2 2022-04-01 OER252949 pdac_3t OEX016414 OES138551 2 2022-04-01 OER252950 pdac_4b OEX016414 OES138552 2 2022-04-01 OER252951 pdac_4t OEX016414 OES138553 2 2022-04-01 OER252952 pdac_5b OEX016414 OES138554 2 2022-04-01 OER252953 pdac_5t OEX016414 OES138555 2 2022-04-01 - Analysis
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1
Analysis ID Analysis Title Analysis Type Data Date OEZ013913 GUT_PDAC_exp Other 3 2023-04-28
Author Information
- Create Date
- 2022-03-30
- Last Modified
- 2022-12-27
- Submission
- Yuting Dai
- Shanghai Institute of Hematology