Smad3 Promotes Cancer‐Associated Fibroblasts Generation via Macrophage–Myofibroblast Transition

Abstract

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.

RAB26 contributes to the progression of non-small cell lung cancer after being transcriptionally activated by SMAD3

“…Also, there are many studies related to the role of SMAD3 in various cancers. Macrophage-specific silencing of SMAD3 effectively blocks macrophage–myofibroblast transition (MMT), thereby inhibiting cancer-associated fibroblasts (CAF)-mediated cancer progression [ 26 ]. The prostate cancer progression was activated when the SMAD3 was upregulated [ 27 ].…”

LncRNA-Dependent Mechanisms of Transforming Growth Factor-β: From Tissue Fibrosis to Cancer Progression

“…TGF-β1 is well recognized as a key driver of fibrosis and cancer progression, while the roles of TGF-β2 and TGF-β3 are still largely unclear [20]. TGF-β1 can be directly activated by reactive oxygen species, pH, and proteases in various contexts such as tissue injury, stress, viral infection, carcinogenesis, tissue fibrosis, and inflammation [21,22]. TGF-β1 peptide is expressed and secreted as a nonactive complex with latent TGF-β binding protein that is cleaved to release active TGF-β1 [17] for TGF-β1 receptor type II binding, triggering downstream signaling via TGF-β1 receptor type I kinase (TβRI) [23].…”

“…TGF-β1 signaling activation has been associated with metastasis and poorer prognosis due to the induction of EMT and drug resistance [82,83], but disruption of TGF-β1 signaling also leads to poor prognosis and accelerated tumor progression as TGF-β1-induced cancer cell apoptosis was relieved [84]. EMT is induced in epithelial tumor cells with prolonged exposure to TGF-β1, phenotypic changes including the loss of cell-cell adhesion between epithelial cancer cells to allow their migration and invasion, and the acquisition of protumoral cancer-associated fibroblast phenotype [22,85]. Thus, EMT is a critical step in cancer metastasis and a critical contributor to patients' poor prognosis.…”

“…Smad3 is a pathogenic mediator of TGF-β1 signaling in tumor progression [22,[143][144][145]. lncRNAs are associated with the pathogenic action of Smad3 as shown in Table 4.…”

Editorial: Immune Landscape of Kidney Pathology

“…In this Research Topic, Zeng et al systematically summarized the development and application of single-cell RNA-sequencing in kidney immunology. Interestingly, recent work has revealed an unexpected role of macrophage-myofibroblast transition, first identified in kidney fibrosis, in promoting tumor development through tumor-associated macrophage transitioning into cancer-associated fibroblasts in non-small-cell lung carcinoma (Tang et al, 2021b ), suggesting an important contribution of tissue fibrotic pathways in cancer. Therefore, we also opened a new platform in Frontiers for sharing the new insights into fibrotic signaling in cancer ( https://www.frontiersin.org/research-topics/22920/new-insights-into-fibrotic-signaling-in-cancer ).…”