<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Endoplasmic reticulum stress sensor ATF6 as an \r\nimmunometabolic modulator in hepatic \r\ntumorigenesis"^^ . "The liver is the site of the sixth most common form of primary cancer - represented mainly by \r\nhepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Although the recent increment \r\nof knowledge on immunological, metabolic, and genetic mechanisms - from a systemic to a single \r\ncell level approach - led to consistent implementation of the therapeutic management of liver \r\ndiseases and improved quality of life in patients, new challenges became apparent in the \r\ndevelopment of arising therapeutic strategies for pathologies accompanied by chronic \r\ninflammation, like liver cancer. \r\nElevated endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been \r\nobserved in precancerous diseases associated with the development of liver cancer, such as \r\nhepatic viral infection and nonalcoholic steatohepatitis (NASH)1\r\n. In the context of liver diseases, \r\nthe inositol requiring enzyme 1 (IRE1 and the protein kinase R (PKR)–like ER kinase (PERK)\r\nbranches of UPR have been intensively investigated, whereas the role of activating transcription \r\nfactor 6 (ATF6) in hepatic diseases has remained elusive2\r\n. In this study, by employing different \r\ngenetically modified mouse models and cell lines, I tried to examine and illustrate the role of ATF6 \r\nin hepatic tumorigenesis.\r\nIn the first place, I analyzed the publicly available databases of liver cancer, the liver biopsy from \r\nhealthy donors and NASH-diagnosed patients, para-tumor and tumor tissue from liver cancer \r\npatients, and tissues from liver cancer mouse models for the expression of ATF6 at both mRNA \r\nand protein levels. Strikingly, I detected a significant increase in ATF6 mRNA and protein \r\nexpression in the diseased areas compared to their corresponding controls. Moreover, by doing \r\nimmunohistochemistry, I identified the activation of ATF6 in the diseased tissues, indicated by the \r\nnuclear localization of ATF6. Based on these observations, I worked on the generation of \r\nhepatocyte-specific nuclear-ATF6 (nATF6) overexpression mice.\r\nIn a mouse model of hepatocyte-specific activation of the ATF6 branch of UPR, I observed that \r\ntransgenic homozygous mice die shortly after birth, whereas their heterozygous counterparts can \r\nsurvive for more than one year instead, suggesting a dose-effect. Heterozygous mice develop \r\nhepatomegaly, liver damage, and cholestasis at their young ages. Strikingly, the heterozygous \r\nmice progress to liver cancer with a tumor incidence of 100% at 12 months. To investigate the \r\nunderlying mechanisms of the pro-tumorigenic effects by persistent ATF6 activation, I performed \r\nRNA-seq, proteomic and metabolic analysis on the liver of the heterozygous animals. I found out \r\nthat ATF6 is intensively involved in the regulation of hepatic glucose, lipid, and amino acid metabolism. The sustained activation of the ATF6 arm of UPR in hepatocytes induces hepatocyte \r\ncell death and shifts the cellular metabolism to support the energy and building blocks \r\nrequirements for compensatory proliferation. The high rate of hepatocyte turnover and constant \r\nER stress lead to oxidative stress and hepatic inflammation, resulting in hepatic tumor onset. \r\nMeanwhile, the metabolic switch in hepatocytes deprives nutrients in the surrounding environment\r\nand further suppresses the anti-tumor function of immune cells.\r\nIn the end, I generated hepatocyte-specific ATF6 knockout mice, and I challenged this mouse \r\nmodel with different carcinogenic treatments. Surprisingly, I found ATF6 knockout confers general \r\nhepato-protection to mice in response to these treatments, indicating a potential clinical \r\napplication of ATF6 inhibition in anti-tumor therapies"^^ . "2023" . . . . . . . "Xin"^^ . "Li"^^ . "Xin Li"^^ . . . . . . "Endoplasmic reticulum stress sensor ATF6 as an \r\nimmunometabolic modulator in hepatic \r\ntumorigenesis (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Endoplasmic reticulum stress sensor ATF6 as an \r\nimmunometabolic modulator in hepatic \r\ntumorigenesis (Other)"^^ . . . . . . "small.jpg"^^ . . . "Endoplasmic reticulum stress sensor ATF6 as an \r\nimmunometabolic modulator in hepatic \r\ntumorigenesis (PDF)"^^ . . . "PhD Thesis Xin Li upload.pdf"^^ . . . "Endoplasmic reticulum stress sensor ATF6 as an \r\nimmunometabolic modulator in hepatic \r\ntumorigenesis (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Endoplasmic reticulum stress sensor ATF6 as an \r\nimmunometabolic modulator in hepatic \r\ntumorigenesis (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Endoplasmic reticulum stress sensor ATF6 as an \r\nimmunometabolic modulator in hepatic \r\ntumorigenesis (Other)"^^ . . . . . . "preview.jpg"^^ . . "HTML Summary of #30890 \n\nEndoplasmic reticulum stress sensor ATF6 as an \nimmunometabolic modulator in hepatic \ntumorigenesis\n\n" . "text/html" . .