Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage-Myofibroblast Transition in Non-Small-Cell Lung Carcinoma.
Philip Chiu-Tsun TangMax Kam-Kwan ChanJeff Yat-Fai ChungAlex Siu-Wing ChanDongmei ZhangChunjie LiKam-Tong LeungCalvin Sze-Hang NgYi WuKa-Fai ToHui-Yao LanPatrick Ming-Kuen TangPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2023)
Macrophage-myofibroblast transition (MMT) is a newly discovered pathway for mass production of pro-tumoral cancer-associated fibroblasts (CAFs) in non-small cell lung carcinoma (NSCLC) in a TGF-β1/Smad3 dependent manner. Better understanding its regulatory signaling in tumor microenvironment (TME) may identify druggable target for the development of precision medicine. Here, by dissecting the transcriptome dynamics of tumor-associated macrophage at single-cell resolution, a crucial role of a hematopoietic transcription factor Runx1 in MMT formation is revealed. Surprisingly, integrative bioinformatic analysis uncovers Runx1 as a key regulator in the downstream of MMT-specific TGF-β1/Smad3 signaling. Stromal Runx1 level positively correlates with the MMT-derived CAF abundance and mortality in NSCLC patients. Mechanistically, macrophage-specific Runx1 promotes the transcription of genes related to CAF signatures in MMT cells at genomic level. Importantly, macrophage-specific genetic deletion and systemic pharmacological inhibition of TGF-β1/Smad3/Runx1 signaling effectively prevent MMT-driven CAF and tumor formation in vitro and in vivo, representing a potential therapeutic target for clinical NSCLC.
Keyphrases
- transcription factor
- transforming growth factor
- single cell
- epithelial mesenchymal transition
- rna seq
- small cell lung cancer
- adipose tissue
- dna binding
- genome wide identification
- genome wide
- bone marrow
- advanced non small cell lung cancer
- end stage renal disease
- high throughput
- ejection fraction
- gene expression
- copy number
- stem cells
- prognostic factors
- peritoneal dialysis
- patient reported outcomes
- mesenchymal stem cells
- type diabetes
- cell proliferation
- epidermal growth factor receptor
- drug induced
- extracellular matrix
- patient reported
- bioinformatics analysis