Similar Datasets
Project description:Liver dysfunction is associated with diseases ranging from metabolic disorders to hepatocellular carcinomas (HCC). Here we employed single-cell RNA-sequencing to extensively characterise the cellular landscape of human liver, from development to disease. We analysed ~212,000 cells representing human fetal liver, HCC and mouse liver. Our analysis revealed a remarkable fetal-like reprogramming of the tumor microenvironment (TME). Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including the re-emergence of fetal-associated endothelial cells (PLVAP+/VEGFR2+), and fetal-like (FOLR2+) tumor-associated macrophages (TAMs). In a cross-species comparative analysis, we discovered remarkable similarity of gene expression and regulatory networks between mouse embryonically-seeded, fetal-liver and FOLR2+ tumor macrophages. Spatial transcriptomics further corroborated a shared onco-fetal ecosystem between fetal-liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem between the human fetal-liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of tumor ecosystem, provides a novel target for therapeutic interventions in HCC and also opens up avenues for identifying similar paradigms in other cancers and disease states.
2020-09-24 | GSE156626 | GEO
Project description:Liver dysfunction is associated with diseases ranging from metabolic disorders to hepatocellular carcinomas (HCC). Here we employed single-cell RNA-sequencing to extensively characterise the cellular landscape of human liver, from development to disease. We analysed ~212,000 cells representing human fetal liver, HCC and mouse liver. Our analysis revealed a remarkable fetal-like reprogramming of the tumor microenvironment (TME). Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including the re-emergence of fetal-associated endothelial cells (PLVAP+/VEGFR2+), and fetal-like (FOLR2+) tumor-associated macrophages (TAMs). In a cross-species comparative analysis, we discovered remarkable similarity of gene expression and regulatory networks between mouse embryonically-seeded, fetal-liver and FOLR2+ tumor macrophages. Spatial transcriptomics further corroborated a shared onco-fetal ecosystem between fetal-liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem between the human fetal-liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of tumor ecosystem, provides a novel target for therapeutic interventions in HCC and also opens up avenues for identifying similar paradigms in other cancers and disease states.
2020-09-24 | GSE156625 | GEO
Project description:Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in Hepatocellular Carcinoma
| PRJNA658535 | ENA
Project description:Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in Hepatocellular Carcinoma (Nanostring)
| PRJNA658540 | ENA
Project description:Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in Hepatocellular Carcinoma (scRNA-seq)
| PRJNA658541 | ENA
Project description:Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Here, we show that an androgen receptor (AR)-driven oncogene, cell cycle-related kinase (CCRK), collaborates with obesity-induced pro-inflammatory signaling to promote non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Lentivirus-mediated Ccrk ablation in liver of male mice fed with high-fat high-carbohydrate diet abrogates not only obesity-associated lipid accumulation, glucose intolerance and insulin resistance, but also HCC development. Mechanistically, CCRK fuels a feedforward loop by inducing STAT3-AR promoter co-occupancy and transcriptional up-regulation, which in turn activates mTORC1/4E-BP1/S6K/SREBP1 cascades via GSK3? phosphorylation. Moreover, hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G-csf expression to enhance polymorphonuclear myeloid-derived suppressor cell recruitment and tumorigenicity. Finally, the STAT3-AR-CCRK-mTORC1 pathway components are concordantly over-expressed in human NASH-associated HCCs. These findings unveil the dual roles of an inflammatory-CCRK circuitry in driving metabolic and immunosuppressive reprogramming through mTORC1 activation, thereby establishing a pro-tumorigenic microenvironment for HCC development.
| S-EPMC6283830 | biostudies-other
Project description:Background and aimsPyruvate kinase M2 (PKM2) is an essential regulator of the Warburg effect, but its biological function promoting immune escape of hepatocellular carcinoma (HCC) is unclear.MethodsGEPIA web tool and immunohistochemistry (IHC) analysis were employed to evaluate the clinical relevance of PKM2 in HCC patients. Both in vitro CCK-8, colony formation, and transwell assays, and in vivo xenografts were performed to evaluate the malignancy of HCC cells. PKM2 and PD-L1 levels were examined by Western blot, qRT-PCR, and IHC. The role of PKM2 on in vivo immune response was also investigated.ResultsPKM2 was significantly upregulated in HCC and associated with a poor prognosis of HCC patients. Knockdown of PKM2 inhibited in vitro proliferation, migration, and invasion of HCC cells, as well as in vivo tumor growth. Strikingly, PKM2 showed a strong correlation with the expression of immune inhibitory cytokines and lymphocyte infiltration in HCC. The overexpression of PKM2 sensitized HCC to immune checkpoint blockade, which enhanced IFN-γ positive CD8 T cells in HCC mice models.ConclusionPKM2 might be a predictor and a potential therapeutic target for immune checkpoint inhibitors in HCC.
| S-EPMC7606949 | biostudies-literature
Project description:BackgroundMitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear.MethodsThe mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo.ResultsMitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-D-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1.ConclusionsOur results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.
| S-EPMC7052272 | biostudies-literature
Project description:Galectin-1 (Gal-1) is a secretory lectin with pro-tumor activities and is associated strongly with hepatocellular carcinoma (HCC) development. Although Gal-1 is a well-known soluble pro-tumor factor in the tumor microenvironment (TME), the secretion mode of Gal-1 is not clearly defined. On the other hand, in addition to cancer cells, Gal-1 is widely expressed in tumor stromal cells, including tumor-associated macrophages (TAMs). TAMs are a significant component of stromal cells in TME; however, their contributions in producing Gal-1 to TME are still not explored. Here we reveal that TAMs can actively secrete Gal-1 in response to stimuli of HCC cells. Gal-1 produced by TAMs leads to an increase of the systemic level of Gal-1 and HCC tumor growth in mice. Mechanistically, TLR2-dependent secretory autophagy is found to be responsible for Gal-1 secretion from TAMs. Gal-1 acts as a cargo of autophagosomes to fuse with multivesicular bodies via Rab11 and VAMP7-mediated vesicle trafficking before being secreted. This autophagy-regulated Gal-1 secretion in TAMs correlates to poor overall survival and progression-free survival rates of HCC patients. Our findings uncover the secretion mode of Gal-1 via secretory autophagy and highlight the pathological role of TAM-produced Gal-1 in HCC progression.
| S-EPMC8450461 | biostudies-literature
Project description:BackgroundTumor-associated macrophages (TAM) are immunosuppressive cells that contribute to impaired anti-cancer immunity. Iron plays a critical role in regulating macrophage function. However, it is still elusive whether it can drive the functional polarization of macrophages in the context of cancer and how tumor cells affect the iron-handing properties of TAM. In this study, using hepatocellular carcinoma (HCC) as a study model, we aimed to explore the effect and mechanism of reduced ferrous iron in TAM.MethodsTAM from HCC patients and mouse HCC tissues were collected to analyze the level of ferrous iron. Quantitative real-time PCR was used to assess M1 or M2 signature genes of macrophages treated with iron chelators. A co-culture system was established to explore the iron competition between macrophages and HCC cells. Flow cytometry analysis was performed to determine the holo-transferrin uptake of macrophages. HCC samples from The Cancer Genome Atlas (TCGA) were enrolled to evaluate the prognostic value of transferrin receptor (TFRC) and its relevance to tumor-infiltrating M2 macrophages.ResultsWe revealed that ferrous iron in M2-like TAM is lower than that in M1-like TAM. In vitro analysis showed that loss of iron-induced immunosuppressive M2 polarization of mouse macrophages. Further experiments showed that TFRC, the primary receptor for transferrin-mediated iron uptake, was overexpressed on HCC cells but not TAM. Mechanistically, HCC cells competed with macrophages for iron to upregulate the expression of M2-related genes via induction of HIF-1α, thus contributing to M2-like TAM polarization. We further clarified the oncogenic role of TFRC in HCC patients by TCGA. TFRC is significantly increased in varieties of malignancies, including HCC, and HCC patients with high TFRC levels have considerably shortened overall survival. Also, TFRC is shown to be positively related to tumor-infiltrating M2 macrophages.ConclusionsCollectively, we identified iron starvation through TFRC-mediated iron competition drives functional immunosuppressive polarization of TAM, providing new insight into the interconnection between iron metabolism and tumor immunity.
| S-EPMC8361643 | biostudies-literature