Project description:Tumor-specific metabolic rewiring, intended to confer a survival advantage over non-transformed cells, often offers an opportunity to target cancers. Here, we identify deregulated expression of purine biosynthetic enzymes as a metabolic hallmark in human hepatocellular carcinomas (HCC), with the extent of enzyme upregulation a predictor of clinical outcome. We demonstrate in HCC cell lines, patient-derived xenograft (PDX) organoids and mouse models that inhibition of purine biosynthesis abrogated cancer cell proliferation and tumor growth. Mechanistically, a PI3K-E2F1 axis coordinated purine biosynthetic enzyme expression. Clinically approved inhibitors against PI3K and the purine biosynthetic rate-limiting enzyme IMPDH synergistically reduced the tumor burden in a PDX mouse model. Collectively, our results support targeting purine metabolic reprogramming as a precision therapeutic strategy for HCC patients.
Project description:We employed bulk RNA-sequencing to compare gene expression between the two major phenotypic subsets of disease-associated macrophages based on MHCII protein expression as well as tissue-resident macrophages and disease-monocytes.
Project description:Analysis of gene expression in explanted peritoneal macrophages from Aoah -/- and Aoah +/+ mice treated with LPS 21 days prior to harvest. Explanted peritoneal machrophages were challenged with LPS or control (PBS). The study seeks to characterize global gene expression in the state of prolonged LPS tolerance induced in mice lacking the LPS-inactivating enzyme Aoah.
Project description:Analysis of gene expression in explanted peritoneal macrophages from Aoah -/- and Aoah +/+ mice treated with LPS 21 days prior to harvest. Explanted peritoneal machrophages were challenged with LPS or control (PBS). The study seeks to characterize global gene expression in the state of prolonged LPS tolerance induced in mice lacking the LPS-inactivating enzyme Aoah. Groups of 9 C57BL/6 Aoah+/+ or Aoah-/- mice were given i.p. injections of 10 µg E. coli LPS/mouse. Twenty-one days later (when Aoah-/- mice remain tolerant and Aoah+/+ mice have recovered), peritoneal macrophages were harvested and the yields from three mice were pooled to form 3 samples per group (i.e., three samples of Aoah+/+ and Aoah-/- mice, with each sample comprised of peritoneal macrophages from 3 mice). Next day, cells were challenged with LPS or PBS and whole RNA was isolated 2 hours later and used for microarray experiments.
Project description:The fatty acid synthase (FASN) is the major fat synthesizing enzyme. FASN is an indispensable enzyme because mice with genetic deletion of Fasn are not viable. Apart from its physiological function, previous studies indicated that FASN could also exert a pathophysiological role, in the heart, because patients with heart failure showed up-reguation of FASN. To investigate the in vivo function of FASN up-regulation in the heart, we generated mice with myocardium-specific expression of FASN under control of the alpha-MHC promoter. Two different founder lines were generated with high and low FASN over-expression. Microarray gene expression profiling of heart tissue was performed of heart tissue from transgenic mice with high and low FASN expression
Project description:A variety of important anticancer drugs kill cells by increasing cellular levels of topoisomerase II-DNA cleavage complex. The anthracycline anticancer drug doxorubicin forms a stable ternary complex with DNA and topoisomerase IIa, thereby inhibiting the normal function of the enzyme. In this study we found genes regulated by doxorubicin - induced and repressed - to be located much closer to each other than genes distributed randomly all over the genome (< 100 kbp). Keywords: Doxorubicin-treated human hepatocytes versus non-treated human hepatocytes