ORCID Profile
0000-0001-7764-577X
Current Organisation
University of Cambridge
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Publisher: Elsevier BV
Date: 03-2021
Publisher: Research Square Platform LLC
Date: 25-04-2023
DOI: 10.21203/RS.3.RS-2842963/V1
Abstract: Oncogenic RAS-induced senescence (OIS) is an autonomous tumour suppressor mechanism associated with pre-malignancy 1-3 . Achieving this phenotype typically requires a high level of oncogenic stress, yet the phenotype provoked by lower oncogenic dosage remains unclear. Here we develop oncogenic RAS-dose escalation models in vitro and in vivo, revealing a RAS-dose-driven non-linear continuum of downstream phenotypes. In a hepatocyte OIS model in vivo, where ectopic expression of NRAS G12V fails to induce tumours in part due to OIS-driven immune clearance 4 . scRNA-seq analyses reveal distinct hepatocyte clusters with typical OIS or progenitor-like features, corresponding to high- and intermediate-NRAS G12V levels, respectively. Remarkably, when titered down, NRAS G12V -expressing hepatocytes become immune-resistant, and develop tumours. Time-series monitoring at single-cell resolution identifies two distinct tumour types: early-onset aggressive undifferentiated and late-onset differentiated hepatocellular carcinoma (HCC). The molecular signature of each murine tumour type is associated with different progenitor features and enriched in distinct human HCC subclasses. Our results define the oncogenic dosage-driven OIS spectrum, reconciling the senescence and tumour initiation phenotypes in early tumorigenesis.
Publisher: Cold Spring Harbor Laboratory
Date: 05-2022
Abstract: Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss of Rela prevents development of Stat1-expressing CD4 + T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS–ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.
Publisher: Research Square Platform LLC
Date: 28-12-2020
DOI: 10.21203/RS.3.RS-120562/V1
Abstract: Cellular senescence is a fate-determined state, accompanied by reorganization of heterochromatin. While lineage-appropriate genes can be temporarily repressed through facultative heterochromatin, stable silencing of lineage-inappropriate genes often involves the constitutive heterochromatic mark, histone H3K9me3. The fate of these heterochromatic genes during the chromatin reorganization accompanying senescence is unclear. Here we show a small number of lineage-inappropriate genes are derepressed in senescent cells from H3K9me3 regions that gain open chromatin marks. DNA FISH experiments reveal that these gene loci, which are tightly condensed at the nuclear periphery in proliferative cells, are physically decompacted during senescence. Among these gene loci, NLRP3 is predominantly expressed in immune cells, such as macrophages, where it resides within an open topologically associated domain (TAD). In contrast, NLRP3 is derepressed in senescent fibroblasts, potentially due to the local disruption of the H3K9me3-rich TAD that contains it. The role of NLRP3 has been implicated in the lification of inflammatory cytokine signalling in senescence and aging, underscoring the functional relevance of gene induction from ‘permissive’ H3K9me3 regions in senescent cells.
Publisher: Springer Science and Business Media LLC
Date: 09-05-2018
DOI: 10.1038/S41467-018-04283-9
Abstract: Senescent cells interact with the surrounding microenvironment achieving erse functional outcomes. We have recently identified that NOTCH1 can drive ‘lateral induction’ of a unique senescence phenotype in adjacent cells by specifically upregulating the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells exhibit a massive increase in chromatin accessibility. NOTCH signalling suppresses SAHF and increased chromatin accessibility in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, drive similar chromatin architectural changes in adjacent cells through cell–cell contact. Mechanistically, we show that NOTCH signalling represses the chromatin architectural protein HMGA1, an association found in multiple human cancers. Thus, HMGA1 is involved not only in SAHFs but also in RIS-driven chromatin accessibility. In conclusion, this study identifies that the JAG1–NOTCH–HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.4161/AUTO.19496
Publisher: Springer Science and Business Media LLC
Date: 27-11-2020
DOI: 10.1038/S41467-020-19878-4
Abstract: Senescence is a state of stable proliferative arrest, generally accompanied by the senescence-associated secretory phenotype, which modulates tissue homeostasis. Enhancer-promoter interactions, facilitated by chromatin loops, play a key role in gene regulation but their relevance in senescence remains elusive. Here, we use Hi-C to show that oncogenic RAS-induced senescence in human diploid fibroblasts is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks often at the 3′ end of a subset of active genes. RAS-induced de novo cohesin peaks are transcription-dependent and enriched for senescence-associated genes, exemplified by IL1B , where de novo cohesin binding is involved in new loop formation. Similar IL1B induction with de novo cohesin appearance and new loop formation are observed in terminally differentiated macrophages, but not TNFα-treated cells. These results suggest that RAS-induced senescence represents a cell fate determination-like process characterised by a unique gene expression profile and 3D genome folding signature, mediated in part through cohesin redistribution on chromatin.
Publisher: Springer Science and Business Media LLC
Date: 23-12-2221
Publisher: Wiley
Date: 20-11-2022
Abstract: Multicellular cancer spheroids (MCSs) have emerged as a promising in vitro model that recaptures many features of solid tumours in vivo. To generate cancer spheroids, cells are encapsulated in microgels with high throughput. While the biophysical properties of the cancer spheroid and biomaterial influence the function and behavior of the cells, characterization of these properties remains largely unexplored. In addition, many existing techniques lack control over cell positioning, resulting in the formation of spheroids with large variability. Herein, a versatile, microfluidic platform for generating biocompatible core–shell microgels with uniform cancer spheroids is reported. In addition, an in situ micromechanics measuring device to determine the stiffness of in idual artificial cancer niches is used. The power of the microfluidics‐based method by making MCS‐laden microgels to model the interactions of stromal cancer cells is demonstrated. Together with in vivo data, it is shown that tumor cell proliferation is promoted by cocultured fibroblasts.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-05-2011
Abstract: A cellular compartment allows simultaneous protein synthesis and degradation.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2020
Publisher: Elsevier BV
Date: 04-2010
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NG.3662
Abstract: G-quadruplex (G4) structural motifs have been linked to transcription, replication and genome instability and are implicated in cancer and other diseases. However, it is crucial to demonstrate the bona fide formation of G4 structures within an endogenous chromatin context. Herein we address this through the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We find ∼10,000 G4 structures in human chromatin, predominantly in regulatory, nucleosome-depleted regions. G4 structures are enriched in the promoters and 5' UTRs of highly transcribed genes, particularly in genes related to cancer and in somatic copy number lifications, such as MYC. Strikingly, de novo and enhanced G4 formation are associated with increased transcriptional activity, as shown by HDAC inhibitor-induced chromatin relaxation and observed in immortalized as compared to normal cellular states. Our findings show that regulatory, nucleosome-depleted chromatin and elevated transcription shape the endogenous human G4 DNA landscape.
Publisher: Oxford University Press (OUP)
Date: 09-10-2018
DOI: 10.1093/BIOINFORMATICS/BTY845
Abstract: The overwhelming size and rapid growth of the biomedical literature make it impossible for scientists to read all studies related to their work, potentially leading to missed connections and wasted time and resources. Literature-based discovery (LBD) aims to alleviate these issues by identifying implicit links between disjoint parts of the literature. While LBD has been studied in depth since its introduction three decades ago, there has been limited work making use of recent advances in biomedical text processing methods in LBD. We present LION LBD, a literature-based discovery system that enables researchers to navigate published information and supports hypothesis generation and testing. The system is built with a particular focus on the molecular biology of cancer using state-of-the-art machine learning and natural language processing methods, including named entity recognition and grounding to domain ontologies covering a wide range of entity types and a novel approach to detecting references to the hallmarks of cancer in text. LION LBD implements a broad selection of co-occurrence based metrics for analyzing the strength of entity associations, and its design allows real-time search to discover indirect associations between entities in a database of tens of millions of publications while preserving the ability of users to explore each mention in its original context in the literature. Evaluations of the system demonstrate its ability to identify undiscovered links and rank relevant concepts highly among potential connections. The LION LBD system is available via a web-based user interface and a programmable API, and all components of the system are made available under open licenses from the project home page lbd.lionproject.net. Supplementary data are available at Bioinformatics online.
Publisher: Informa UK Limited
Date: 02-01-2016
Publisher: Elsevier BV
Date: 07-2012
Publisher: Cold Spring Harbor Laboratory
Date: 30-10-2019
DOI: 10.1101/823831
Abstract: Senescence is a phenotypic state of stable proliferative arrest, typically occurring in lineage-committed cells and triggered by various stimuli. It is generally accompanied by activation of a secretory program (senescence-associated secretory phenotype, SASP), which modulates both local (tissue microenvironment) and systemic (ageing) homeostasis 1,2 . Enhancer-promoter interactions play a key role in gene regulation 3–5 , facilitated by chromatin loops, mostly formed via CCCTC binding factor (CTCF) and cohesin tethering 6–8 . The three-dimensional chromatin structure of senescent cells has been characterised 9–11 mostly in terms of macro-domain structures, but its relevance in gene expression remains elusive. Here, we use Hi-C and capture Hi-C 12,13 to show that oncogenic HRAS-induced senescence (RIS) in human diploid fibroblasts (HDFs) is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks at the 3’ end of a subset of active genes, reminiscent of the transcription-driven ‘cohesin islands’ recently discovered in mouse embryonic fibroblasts deficient in both CTCF and the cohesin release factor Wings apart-like (Wapl) 14 . RIS de novo cohesin peaks are also transcription-dependent and enriched for SASP genes, as exemplified by IL1B , where de novo cohesin binding is involved in new loop formation. Cytokine induction is associated with similar cohesin islands appearance and enhancer-promoter rewiring during the terminal differentiation of monocytes to macrophages 15 , but not upon acute TNFα treatment of HDFs 16 . These results suggest that RIS represents a fate-determined process in which gene expression is regulated beyond the cell type specific 3D chromatin framework, in part through cohesin redistribution.
Publisher: Public Library of Science (PLoS)
Date: 19-03-2015
Publisher: EMBO
Date: 28-12-2020
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Masashi Narita.