Dissecting intratumoral myeloid cell plasticity by single cell RNA-seq.
intercellular interaction
monocyte-to-M2 differentiation
non-small cell lung cancer (NSCLC)
single-cell RNA sequencing (scRNA-seq)
trajectory analysis
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
08
01
2019
revised:
07
03
2019
accepted:
08
03
2019
pubmed:
30
4
2019
medline:
14
8
2020
entrez:
30
4
2019
Statut:
ppublish
Résumé
Tumor-infiltrating myeloid cells are the most abundant leukocyte population within tumors. Molecular cues from the tumor microenvironment promote the differentiation of immature myeloid cells toward an immunosuppressive phenotype. However, the in situ dynamics of the transcriptional reprogramming underlying this process are poorly understood. Therefore, we applied single cell RNA-seq (scRNA-seq) to computationally investigate the cellular composition and transcriptional dynamics of tumor and adjacent normal tissues from 4 early-stage non-small cell lung cancer (NSCLC) patients. Our scRNA-seq analyses identified 11 485 cells that varied in identity and gene expression traits between normal and tumor tissues. Among these, myeloid cell populations exhibited the most diverse changes between tumor and normal tissues, consistent with tumor-mediated reprogramming. Through trajectory analysis, we identified a differentiation path from CD14+ monocytes to M2 macrophages (monocyte-to-M2). This differentiation path was reproducible across patients, accompanied by increased expression of genes (eg, MRC1/CD206, MSR1/CD204, PPARG, TREM2) with significantly enriched functions (Oxidative phosphorylation and P53 pathway) and decreased expression of genes (eg, CXCL2, IL1B) with significantly enriched functions (TNF-α signaling via NF-κB and inflammatory response). Our analysis further identified a co-regulatory network implicating upstream transcription factors (JUN, NFKBIA) in monocyte-to-M2 differentiation, and activated ligand-receptor interactions (eg, SFTPA1-TLR2, ICAM1-ITGAM) suggesting intratumoral mechanisms whereby epithelial cells stimulate monocyte-to-M2 differentiation. Overall, our study identified the prevalent monocyte-to-M2 differentiation in NSCLC, accompanied by an intricate transcriptional reprogramming mediated by specific transcriptional activators and intercellular crosstalk involving ligand-receptor interactions.
Identifiants
pubmed: 31033233
doi: 10.1002/cam4.2113
pmc: PMC6558497
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3072-3085Subventions
Organisme : NCI NIH HHS
ID : R01 CA131231
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172115
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA012197
Pays : United States
Informations de copyright
© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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