TGF-β1-mediated transition of resident fibroblasts to cancer-associated fibroblasts promotes cancer metastasis in gastrointestinal stromal tumor

Abstract

Cancer-associated fibroblasts (CAFs) are the most abundant cells in the tumor microenvironment. Crosstalk between tumor cells and CAFs contributes to tumor survival in most epithelial cancers. Recently, utilizing gastrointestinal stromal tumor (GIST) as a model for sarcomas, we identified paracrine networks by which CAFs promote tumor progression and metastasis. However, the mechanisms by which CAFs arise in sarcomas remain unclear. Here, RNA sequencing analysis revealed that transforming growth factor-β1 (TGF-β1) is highly expressed in both tumor cells and CAFs. To determine the functional role of TGF-β1, we treated normal gastric fibroblasts (GFs) with recombinant TGF-β1, which caused the GFs to adopt a more stellate morphology, as well as increased the mRNA expression of CAF-mediated genes (CCL2, RAB3B, and TNC) and genes encoding fibroblast growth factors (FGFs). Moreover, while either GIST or CAF conditioned media enhanced the transition from GFs to CAFs, a TGF-β1-blocking antibody attenuated this effect. Transwell migration assays revealed that the TGF-β1-mediated transition from GFs to CAFs enhanced tumor cell migration. This migratory effect was abrogated by an anti-TGF-β1 antibody, suggesting that TGF-β1 secreted from GIST cells or CAFs is associated with GIST migration via GF-to-CAF transition. In addition, the murine spleen-to-liver metastasis model showed that GF pre-treated with TGF-β1 promoted GIST metastasis. Collectively, these findings reveal unappreciated crosstalk among tumor cells, CAFs, and normal resident fibroblasts in the stroma of sarcomas, which enhances a GF-to-CAF transition associated with tumor migration and metastasis.

Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

“…CAFs can be derived from normal resident tissue fibroblasts that are activated by adjacent tumor cells. A majority of stromal activated fibroblasts initially originate from local resident fibroblasts, which respond to TGFb and undergo myofibroblastic differentiation during tissue wound healing and cancer progression (7)(8)(9). Bone marrow-derived mesenchymal stem cells (MSCs) are a source of CAFs via recruitment by tumor cell secreted factors.…”

Perturb-map enables CRISPR genomics with spatial resolution and identifies regulators of tumor immune composition

“…In Tgfbr2 KO tumors there was an increase of various collagen-coding genes, including Col1a1, Col6a1, and Col6a2 ( Figure 5D and 5E ), consistent with the presence of a fibro-mucinous stroma ( Figure 3H and Figure 3I ). Unexpectedly, many of the genes upregulated in the Tgfbr2-targeted tumors were indicative of increased TGFβ signaling, including Tnc, Timp1, and Arg1, which are induced by TGFβ (Calon et al, 2012; Kwak et al, 2006; Mondanelli et al, 2017; Yoon et al, 2021) ( Figure 5E ). There was also downregulation of Sftpb, which is negatively regulated by TGFβ (Wesselkamper et al, 2005).…”

Cancer-Secreted Exosomal HSPC111 Promotes Colorectal Cancer Liver Metastasis By Reprogramming Lipid Metabolism in Cancer-Associated Fibroblasts

“…In recent years, multiple studies have shown that CAFs crosstalk with cancer cells via secreting various cytokines and chemokines [46,47] , and other studies have demonstrated that metabolic reprogramming of CAFs are important in cancer progress [48] . For example, TGF-β1 secreted by CAFs is associated with gastrointestinal stromal tumor migration and metastasis [49] . Moreover, lactate secreted from CAFs could be absorbed by prostate cancer cells and promote their growth [50] .…”