期刊
ADVANCED SCIENCE
卷 9, 期 1, 页码 -出版社
WILEY
DOI: 10.1002/advs.202101235
关键词
cancer-associated fibroblasts; macrophage-myofibroblast transition; Smad3; tumor-associated macrophages; tumor microenvironment
资金
- Research Grants Council of Hong Kong [RGC 14111720, 14106518, 14111019, 14121816, 14117418, 14104019, C7018-16G]
- Innovation and Technology Fund of Hong Kong [ITS/068/18]
- Faculty Innovation Award CUHK [4620528]
- Direct Grant for Research CUHK [4054386, 4054440]
- Lui Che Woo Institute of Innovative Medicine (CARE program)
- Guangdong-Hong Kong-Macao-Joint Labs Program from Guangdong Science and Technology [2019B121205005]
This study identified a novel role of macrophage-myofibroblast transition (MMT) in cancer, showing that MMT cells can de novo generate cancer-promoting cancer-associated fibroblasts (CAFs). Through fate-mapping, RNA velocity, and pseudotime analysis, a subset of CAFs derived from macrophages was confirmed in the tumor microenvironment. Targeting Smad3, a key regulator in the MMT process, effectively blocked CAF formation and cancer progression in vivo, suggesting MMT as a potential therapeutic target for cancer immunotherapy.
Cancer-associated fibroblasts (CAFs) are important in tumor microenvironment (TME) driven cancer progression. However, CAFs are heterogeneous and still largely underdefined, better understanding their origins will identify new therapeutic strategies for cancer. Here, the authors discovered a new role of macrophage-myofibroblast transition (MMT) in cancer for de novo generating protumoral CAFs by resolving the transcriptome dynamics of tumor-associated macrophages (TAM) with single-cell resolution. MMT cells (MMTs) are observed in non-small-cell lung carcinoma (NSCLC) associated with CAF abundance and patient mortality. By fate-mapping study, RNA velocity, and pseudotime analysis, existence of novel macrophage-lineage-derived CAF subset in the TME of Lewis lung carcinoma (LLC) model is confirmed, which is directly transited via MMT from M2-TAM in vivo and bone-marrow-derived macrophages (BMDM) in vitro. Adoptive transfer of BMDM-derived MMTs markedly promote CAF formation in LLC-bearing mice. Mechanistically, a Smad3-centric regulatory network is upregulated in the MMTs of NSCLC, where chromatin immunoprecipitation sequencing(ChIP-seq) detects a significant enrichment of Smad3 binding on fibroblast differentiation genes in the macrophage-lineage cells in LLC-tumor. More importantly, macrophage-specific deletion and pharmaceutical inhibition of Smad3 effectively block MMT, therefore, suppressing the CAF formation and cancer progression in vivo. Thus, MMT may represent a novel therapeutic target of CAF for cancer immunotherapy.
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