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Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment.

ABSTRACT: Desmoplasia is a hallmark of intrahepatic cholangiocarcinoma (ICC), which constitutes a barrier to infiltration of lymphocyte, but not myeloid cells. Given that dense desmoplastic stroma has been reported to be a barrier to infiltration of lymphocyte, but not myeloid cells. We here investigated whether fibroblastic FAP influenced ICC progression via non-T cell-related immune mechanisms. We demonstrated fibroblastic FAP expression was critical for STAT3 activation and CCL2 production, and ICC-CAFs were the primary source of CCL2 in human ICC microenvironment by using ICC-Fbs from six ICC patients. Fibroblastic knockdown of FAP significantly impaired the ability of ICC-CAFs to promote ICC growth, MDSCs infiltration and angiogenesis, which was restored by adding exogenous CCL2. Furthermore, interestingly, the tumor-promoting effect of fibroblastic FAP is dependent on MDSCs via secretion of CCL2, as depletion of Gr-1+ cells reversed the restoring effects of exogenous CCL2 on tumor growth and angiogenesis. In vitro migration assay confirmed that exogenous CCL2 could rescue the impaired ability of ICC-Fbs to attract Gr-1+ cells caused by fibroblastic FAP knockdown. In contrast, fibroblastic FAP knockdown had no effect on ICC cell proliferation and apoptotic resistance. Depletion MDSCs by anti-Gr-1 monoclonal antibody in subcutaneous transplanted tumor model abrogated tumor promotion by ICC-CAFs suggested that the pro-tumor function of Fibroblastic FAP relied on MDSCs. Mechanical, flow cytometry and chamber migration assay were conducted to find Fibroblastic FAP was required by the ability of ICC-CAFs to promote MDSC migration directly. Moreover, fibroblastic FAP knockdown had no effect on cell proliferation and apoptotic resistance. Here, we revealed the T-cell independent mechanisms underlying the ICC-promoting effect of fibroblastic FAP by attracting MDSCs via CCL2, which was mainly attributed to the ability of FAP to attract MDSCs and suggests that specific targeting fibroblastic FAP may represent a promising therapeutic strategy against ICC.

SUBMITTER: Lin Y

PROVIDER: S-EPMC6880109 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment.

Lin Yuli Y Li Bingji B Yang Xuguang X Cai Qian Q Liu Weiren W Tian Mengxin M Luo Haoyang H Yin Wei W Song Yan Y Shi Yinghong Y He Rui R

Neoplasia (New York, N.Y.) 20191120 12

Desmoplasia is a hallmark of intrahepatic cholangiocarcinoma (ICC), which constitutes a barrier to infiltration of lymphocyte, but not myeloid cells. Given that dense desmoplastic stroma has been reported to be a barrier to infiltration of lymphocyte, but not myeloid cells. We here investigated whether fibroblastic FAP influenced ICC progression via non-T cell-related immune mechanisms. We demonstrated fibroblastic FAP expression was critical for STAT3 activation and CCL2 production, and ICC-CAF ...[more]

PMID: 31759251

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Project description:BackgroundIncreasing evidence shows that circular RNAs (circRNAs), a novel class of noncoding RNAs, play a crucial role in the development of cancers, including intrahepatic cholangiocarcinoma (iCCA). Nevertheless, their functions and exact mechanisms in iCCA progression and metastasis are still unclear. Ipatasertib is a highly selective inhibitor of AKT that inhibits tumor growth by blocking the PI3K/AKT pathway. In addition, phosphatase and tensin homolog (PTEN) can also inhibit the activation of the PI3K/AKT pathway, but it is not clear whether the cZNF215-PRDX-PTEN axis plays a role in the antitumor activity of ipatasertib.MethodsWe identified a new circRNA (circZNF215, termed cZNF215) through high-throughput circRNA sequencing (circRNA-seq). In addition, RT‒qPCR, immunoblot assay, RNA pull-down assay, RNA immunoprecipitation (RIP) assay, and fluorescence in situ hybridization assay (FISH) were used to investigate the interaction of cZNF215 with peroxiredoxin 1 (PRDX1). Coimmunoprecipitation (Co-IP) assays and duolink in situ proximity ligation assays (PLAs) were conducted to analyze the effects of cZNF215 on the interaction between PRDX1 and PTEN. Finally, we tested the potential effects of cZNF215 on the antitumor activity of ipatasertib with in vivo experiments.ResultsWe found that cZNF215 expression was obviously upregulated in iCCA tissues with postoperative metastases and was correlated with iCCA metastasis and poor outcome in patients with iCCA. We further revealed that overexpression of cZNF215 promoted iCCA cell growth and metastasis in vitro and in vivo, while cZNF215 knockdown had the opposite effect. Mechanistic studies suggested that cZNF215 competitively interacted with PRDX1, which blocked the association between PRDX1 and PTEN, subsequently leading to oxidation-induced inactivation of the PTEN/AKT pathway and finally contributing to iCCA progression and metastasis. Additionally, we also revealed that silencing cZNF215 in iCCA cells had the potential to enhance the antitumor effect of ipatasertib.ConclusionsOur study demonstrates that cZNF215 facilitates iCCA progression and metastasis by regulating the PTEN/AKT pathway and may serve as a novel prognostic predictor in patients with iCCA.

Dataset Information

Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment.

Publications

Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment.

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