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TGF-Β1-Mediated Transition of Resident Fibroblasts to Cancer-Associated

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TGF-Β1-Mediated Transition of Resident Fibroblasts to Cancer-Associated Yoon et al. Oncogenesis (2021) 10:13 https://doi.org/10.1038/s41389-021-00302-5 Oncogenesis ARTICLE Open Access TGF-β1-mediated transition of resident fibroblasts to cancer-associated fibroblasts promotes cancer metastasis in gastrointestinal stromal tumor Hyunho Yoon1,2,Chih-MinTang1,2,SudeepBanerjee1,2,3,AntonioL.Delgado1,2,MayraYebra1,2,JacobDavis1,2 and Jason K. Sicklick 1,2 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 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; 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. Introduction sunitinib, regorafenib, and ripretinib are only 7.0%, 4.5%, – A gastrointestinal stromal tumor (GIST), the most and 9.4%, respectively5 7. Due to the high rates of common sarcoma, is most often driven by oncogenic KIT recurrence, alternative therapeutic targets are needed to – or PDGFRA mutations1 3. As a result, anti-KIT/PDGFRA effectively treat GIST. tyrosine kinase inhibitors (TKIs) are commonly used to Cancer-associated fibroblasts (CAFs) are the most treat these tumors. However, 50% of metastatic GISTs abundant cells in the tumor microenvironment (TME). treated with imatinib, the first-line treatment, will develop It is well established that crosstalk between epithelial drug-resistance within 20 months of starting therapy cancers and CAFs can promote tumor progression and – [median progression-free survival (PFS) 20.4 month]4. chemoresistance8 10. Specifically, CAFs can promote a The objective response rates for later line anti-GIST TKIs, favorable biological environment for tumor growth by secreting cytokines, chemokines, and growth factors. Over time, the spatial and temporal interactions of tumor cells Correspondence: Jason K. Sicklick ([email protected]) and stromal cells create a symbiotic relationship in which 1 Department of Surgery, Division of Surgical Oncology, University of California, the tumor receives a growth advantage from the CAFs, San Diego, CA, USA 11 2Moores Cancer Center, University of California, San Diego, CA, USA and vice versa . In addition, our previous study showed Full list of author information is available at the end of the article © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Oncogenesis Yoon et al. Oncogenesis (2021) 10:13 Page 2 of 12 paracrine fibroblastic support in GIST promotes tumor compared mRNA expression of CAF-mediated genes growth and metastasis12. These studies suggest that CAFs (CCL2, RAB3B, and TNC) in GFs and CAFs. CCL2, might be an alternative target for treating both epithelial RAB3B, and TNC have known CAF markers in gene set cancers and sarcomas. enrichment analyses (GSEA; MISHRA_CAF_UP)19. The CAFs originate from various cell types, including resi- expression levels of CCL2, RAB3B, and TNC were also dent fibroblasts, epithelial cells, and bone marrow-derived increased in CAFs compared to GFs (Fig. 1d; Supple- mesenchymal stem cells. Cytokines, chemokines, and mentary Fig. S1c). CM from GIST-T1 cells and CAFs growth factors can enhance their transition into CAFs in resulted in increased mRNA expression of CCL2, RAB3B, – tumor stroma13 15. Transforming growth factor-β1 (TGF- and TNC in GFs (Fig. 1e), suggesting that CM of GIST β1), a ligand of the TGF-β receptor complex, plays and CAFs can promote a GF-to-CAF transition. important roles in many biological processes by activating To further investigate the functional role of PDGFC TGF-β signaling, which promotes tumorigenesis and secreted from CAFs in GIST, a phosphokinase array was – metastasis16 18. Moreover, normal fibroblasts derived probed to compare CM from CAFscramble (scr), from bone marrow-derived mesenchymal stem cells in CAFshPDGFC #1, and CAFshPDGFC #2 in GIST-T1. pancreatic cancer stroma have been reported to transition Notably, CAFscr CM significantly activated several into CAFs in response to TGF-β signaling, which enhances phosphokinase proteins, including JNK1/2/3, AKT, FAK, tumor growth and invasion13. However, little is known PRAS40, c-Jun, and STAT3, while these effects were regarding the role of TGF-β signaling in the stroma of abrogated by loss of PDGFC (Fig. 1f, g). In addition, as sarcomas. shown in supplementary Fig. S1d, CAFs markedly induced Here, we present a detailed mechanism for the transi- phosphorylation of PDGFRA and PDGFRB, while this tion of gastric fibroblasts (GFs) into CAFs in GIST, and effect was decreased by the loss of PDGFC. Because how this transition promotes tumor migration and PDGFC is not known to activate PDGFR-β/β, these metastasis. First, TGF-β1 secretion from GISTs and CAFs results suggested that CAF-mediated PDGFC secretion enhances a transition from normal resident fibroblast to affects both PDGFR-α/α homo-dimerization and PDGFR- CAFs. In turn, these ligand-dependent events lead to α/β hetero-dimerization, supporting our previous finding increased tumor motility. Overall, this study suggests that that CAF-mediated PDGFC secretion enhances GIST the TGF-β1-mediated GF-to-CAF transition in the TME progression and metastasis. Together, these data plays an important role in sarcoma migration and demonstrated that PDGFC could be a CAF marker that metastasis, implying that this paracrine network might be modulates an aggressive phenotype of GIST cells. a potential target for treating sarcomas. FGFs are overexpressed in CAFs Results Next, we performed RNA sequencing analyses (RNA- CAFs and GIST cells induce a GF-to-CAF transition seq) using GIST-T1 cells and CAFs to characterize the Recently, we discovered that there are CAFs in GIST CAFs (GSE143547). Interestingly, RNA-seq revealed that (Supplementary Fig. S1a), and platelet-derived growth genes encoding various fibroblast growth factors (FGFs) factor C (PDGFC) secreted from CAFs promotes tumor were overexpressed in CAFs (Fig. 2a). These genes are progression and metastasis via a paracrine PDGFC- known to be upregulated in many cancers, including PDGFRA-SLUG axis12. Since the CAFs were isolated prostate, breast, and colon cancer, as well as are asso- from gastric GIST, we obtained a commercially available ciated with poor survival by promoting tumor growth, – normal GF line to compare with CAFs. To understand the metastasis, and angiogenesis20 22. Thus, we next eval- differences between resident GFs and CAFs isolated from uated the expression of these FGF genes by qPCR. Among human GIST, we compared the morphology and mRNA them, CAFs expressed more FGF1, FGF5, and FGF9 expression of PDGFC, as a functional biomarker of CAFs, expression than GFs (Fig. 2b). In addition, these FGF- in these cells. We observed that CAFs had a more stellate encoding genes were significantly increased in GFs with morphology and higher expression of PDGFC as com- the application of CM from either GIST-T1 cells or CAFs pared to GFs (Fig. 1a, b). In addition, CAFs from GISTs (Fig. 2c), indicating that the expression of these genes with different mutations (i.e., KIT or PDGFRA) and dis- might influence the GIST phenotype. tinct locations (i.e., stomach and rectum) were isolated and characterized. The quantitative polymerase chain reaction TGF-β1 is highly expressed in GISTs and CAFs (qPCR) analysis showed that PDGFC mRNA was highly TGF-β signaling contributes to various biological pro- expressed in all CAF lines (Supplementary Fig. S1b). cesses that promote tumorigenesis and metastasis16,17.In We then cultured the GFs with either GIST-T1 or CAF pancreatic cancer stroma, for example, normal fibroblasts conditioned media (CM). Both CM increased mRNA convert into CAFs via TGF-β signaling, and this process is expression of PDGFC in GFs (Fig. 1c). In addition, we associated with tumor growth and invasion13.OurRNA-seq Oncogenesis Yoon et al. Oncogenesis (2021) 10:13 Page 3 of 12 Fig. 1 (See legend on next page.) Oncogenesis Yoon et al. Oncogenesis (2021) 10:13 Page 4 of 12 (see figure on previous page) Fig.
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