Cellular senescence is characterized by stable cell cycle arrest and a secretory program that modulates the tissue microenvironment 1 , 2 . Physiologically, senescence serves as a tumor suppressive mechanism that prevents the expansion of premalignant cells 3 , 4 and plays a beneficial role in wound healing responses 5 , 6 . Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes, and osteoarthritis 1 , 7 . Accordingly, elimination of senescent cells from damaged tissues in mice ameliorates symptoms of these pathologies and even promotes longevity 1 , 2 , 8 – 10 . Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells targeting senescent cells can be effective senolytics. We identify the urokinase plasminogen activator receptor (uPAR) 11 as a cell surface protein broadly induced during senescence and demonstrate that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo . uPAR-directed CAR T cells extend the survival of mice harboring lung adenocarcinoma treated with a senescence-inducing drug combination, and restore tissue homeostasis in chemical- or diet-induced liver fibrosis. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.
SUMMARY There are still gaps in our understanding of the complex processes by which p53 suppresses tumorigenesis. Here we describe a novel role for p53 in suppressing the mevalonate pathway, which is responsible for biosynthesis of cholesterol and nonsterol isoprenoids. p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene. A mouse model of liver cancer reveals that downregulation of mevalonate pathway gene expression by p53 occurs in premalignant hepatocytes, when p53 is needed to actively suppress tumorigenesis. Furthermore, pharmacological or RNAi inhibition of the mevalonate pathway restricts the development of murine hepatocellular carcinomas driven by p53 loss. Like p53 loss, ablation of ABCA1 promotes murine liver tumorigenesis and is associated with increased SREBP-2 maturation. Our findings demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated liver tumor suppression and outline the mechanism by which this occurs.
A segmental deletion resulting in gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here we implement CRISPR-Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of either the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC. Notably, overexpression of the wild-type PRKACA was unable to fully recapitulate the oncogenic activity of, implying that FL-HCC does not simply result from enhanced PRKACA expression. Tumorigenesis was significantly enhanced by genetic activation of β-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which causes tissue injury, inflammation, and fibrosis. Our study validates the fusion kinase as an oncogenic driver and candidate drug target for FL-HCC, and establishes a practical model for preclinical studies to identify strategies to treat this disease.
Successfully completing the S phase of each cell cycle ensures genome integrity. Impediment of DNA replication can lead to DNA damage and genomic disorders. In this study, we show a novel function for NDE1, whose mutations cause brain developmental disorders, in safeguarding the genome through S phase during early steps of neural progenitor fate restrictive differentiation. Nde1 mutant neural progenitors showed catastrophic DNA double strand breaks concurrent with the DNA replication. This evoked DNA damage responses, led to the activation of p53-dependent apoptosis, and resulted in the reduction of neurons in cortical layer II/III. We discovered a nuclear pool of Nde1, identified the interaction of Nde1 with cohesin and its associated chromatin remodeler, and showed that stalled DNA replication in Nde1 mutants specifically occurred in mid-late S phase at heterochromatin domains. These findings suggest that NDE1-mediated heterochromatin replication is indispensible for neuronal differentiation, and that the loss of NDE1 function may lead to genomic neurological disorders.DOI: http://dx.doi.org/10.7554/eLife.03297.001
Although TP53 is the most commonly mutated gene in human cancers, the p53-dependent transcriptional programs mediating tumor suppression remain incompletely understood.Here, to uncover critical components downstream of p53 in tumor suppression, we perform unbiased RNAi and CRISPR/Cas9-based genetic screens in vivo. These screens converge upon the p53-inducible gene Zmat3, encoding an RNA-binding-protein, and we demonstrate that ZMAT3 is an important tumor suppressor downstream of p53 in mouse Kras G12D -driven lung and liver cancers and human carcinomas. Integrative analysis of the ZMAT3 RNA-binding landscape and transcriptomic profiling reveals that ZMAT3 directly modulates exon inclusion in transcripts encoding proteins of diverse functions, including the p53 inhibitors MDM4 and MDM2, splicing regulators, and components of varied cellular processes. Interestingly, these exons are enriched in NMD signals, and, accordingly, ZMAT3 broadly affects target transcript stability. Collectively, these studies reveal ZMAT3 as a novel RNA-splicing and homeostasis regulator and key component of p53-mediated tumor suppression.We thank Laurakay Bruhn, Steven Altschuler, Ben Borgo, Peter Sheffield and Carsten Carstens of Agilent Inc. for oligonucleotide synthesis and helpful discussions. We thank Lin He for the Eμ-Myc lymphoma cells, Andreas Strasser and Ana Janic for the Zmat3 null MEFs, and Julien Sage and Aaron Gitler for critical reading of the manuscript.
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