102 results found
Gil J, 2019, Cellular senescence causes ageing, Nature Reviews Molecular Cell Biology, ISSN: 1471-0072
Sogaard P, Gil J, 2019, NAD+: A metabolic knob fine-tuning inflammation during senescence, Nature Metabolism, Vol: 1, Pages: 310-311, ISSN: 2522-5812
The senescence-associated secretory phenotype (SASP) is responsible for the deleterious effects of senescent cells in ageing and cancer. A new study shows that NAD+ metabolism can regulate the pro-inflammatory SASP, thereby promoting tumorigenesis.
Bagnati M, Moreno-Moral A, Ko J-H, et al., 2019, Systems-genetics identifies a macrophage cholesterol network associated with physiological wound healing, JCI insight, Vol: 4, ISSN: 2379-3708
Among other cells, macrophages regulate the inflammatory and reparative phases during wound healing but genetic determinants and detailed molecular pathways that modulate these processes are not fully elucidated. Here, we took advantage of normal variation in wound healing in 1,378 genetically outbred mice, and carried out macrophage RNA-sequencing profiling of mice with extreme wound healing phenotypes (i.e., slow and fast healers, n = 146 in total). The resulting macrophage coexpression networks were genetically mapped and led to the identification of a unique module under strong trans-acting genetic control by the Runx2 locus. This macrophage-mediated healing network was specifically enriched for cholesterol and fatty acid biosynthetic processes. Pharmacological blockage of fatty acid synthesis with cerulenin resulted in delayed wound healing in vivo, and increased macrophage infiltration in the wounded skin, suggesting the persistence of an unresolved inflammation. We show how naturally occurring sequence variation controls transcriptional networks in macrophages, which in turn regulate specific metabolic pathways that could be targeted in wound healing.
Innes AJ, Gil J, 2019, IMR90 ER:RAS: A cell model of oncogene-induced senescence, Methods in Molecular Biology, Vol: 1896, Pages: 83-92, ISSN: 1940-6029
Oncogene-induced senescence (OIS) is a cellular response that limits the replication of cells expressing oncogenes. As a result, OIS is a potent tumor suppressor mechanism limiting cancer progression. Here we describe IMR90 ER:RAS, a widely used model to study OIS in cell culture. This model takes advantage of IMR90 human primary fibroblast infected with a 4-hydroxy-tamoxifen (4-OHT) inducible ER:RAS construct. RAS activation upon 4-OHT treatment results in a coordinated induction of senescence, recapitulating different aspects of the phenotype such as the growth arrest and the establishment of a senescence-associated secretory phenotype (SASP).
Bowling S, Di Gregorio A, Sancho M, et al., 2018, Author correction: P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development, Nature Communications, Vol: 9, ISSN: 2041-1723
The original version of this Article contained an error in the spelling of Juan Pedro Martinez-Barbera, which was incorrectly given as Juan Pedro Martinez Barbera. This error has now been corrected in both the PDF and HTML versions of the Article.
Georgilis A, Klotz S, Hanley CJ, et al., 2018, PTBP1-mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells, Cancer Cell, Vol: 34, Pages: 85-102.e9, ISSN: 1535-6108
Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer.
Bowling S, Di Gregorio A, Sancho M, et al., 2018, P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development, Nature Communications, Vol: 9, ISSN: 2041-1723
Ensuring the fitness of the pluripotent cells that will contribute to future development is important both for the integrity of the germline and for proper embryogenesis. Consequently, it is becoming increasingly apparent that pluripotent cells can compare their fitness levels and signal the elimination of those cells that are less fit than their neighbours. In mammals the nature of the pathways that communicate fitness remain largely unknown. Here we identify that in the early mouse embryo and upon exit from naive pluripotency, the confrontation of cells with different fitness levels leads to an inhibition of mTOR signalling in the less fit cell type, causing its elimination. We show that during this process, p53 acts upstream of mTOR and is required to repress its activity. Finally, we demonstrate that during normal development around 35% of cells are eliminated by this pathway, highlighting the importance of this mechanism for embryonic development.
Apps JR, Carreno G, Gonzalez-Meljem JM, et al., 2018, Tumour compartment transcriptomics demonstrate the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identify the MAPK/ERK pathway as a novel therapeutic target, Acta Neuropathologica, Vol: 135, Pages: 757-777, ISSN: 1432-0533
Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP pat
Herranz N, Gil J, 2018, Mechanisms and functions of cellular senescence, Journal of Clinical Investigation, Vol: 128, Pages: 1238-1246, ISSN: 0021-9738
Cellular senescence is a highly stable cell cycle arrest that is elicited in response to different stresses. By imposing a growth arrest, senescence limits the replication of old or damaged cells. Besides exiting the cell cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement, or autophagy modulation. In addition, senescent cells produce and secrete a complex combination of factors, collectively referred as the senescence-associated secretory phenotype, that mediate most of their non–cell-autonomous effects. Because senescent cells influence the outcome of a variety of physiological and pathological processes, including cancer and age-related diseases, pro-senescent and anti-senescent therapies are actively being explored. In this Review, we discuss the mechanisms regulating different aspects of the senescence phenotype and their functional implications. This knowledge is essential to improve the identification and characterization of senescent cells in vivo and will help to develop rational strategies to modulate the senescence program for therapeutic benefit.
Wagner V, Gil J, 2018, An epigenetic switch: from senescent melanocytes to malignant melanoma (and back), Cancer Cell, Vol: 33, Pages: 162-163, ISSN: 1535-6108
Oncogene-induced senescence is an important barrier during melanomagenesis. In this issue of Cancer Cell, Yu et al. show how elevated expression of structurally unrelated H3K9 demethylases disables senescence and constitutes a liability that can be exploited to restore senescence in melanoma by pharmacological inhibition of these epigenetic regulators.
Gonzalez-Meljem JM, Haston S, Carreno G, et al., 2017, Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma, Nature Communications, Vol: 8, ISSN: 2041-1723
Senescent cells may promote tumour progression through the activation of a senescence-associated secretory phenotype (SASP), whether these cells are capable of initiating tumourigenesis in vivo is not known. Expression of oncogenic β-catenin in Sox2+ young adult pituitary stem cells leads to formation of clusters of stem cells and induction of tumours resembling human adamantinomatous craniopharyngioma (ACP), derived from Sox2− cells in a paracrine manner. Here, we uncover the mechanisms underlying this paracrine tumourigenesis. We show that expression of oncogenic β-catenin in Hesx1+ embryonic precursors also results in stem cell clusters and paracrine tumours. We reveal that human and mouse clusters are analogous and share a common signature of senescence and SASP. Finally, we show that mice with reduced senescence and SASP responses exhibit decreased tumour-inducing potential. Together, we provide evidence that senescence and a stem cell-associated SASP drive cell transformation and tumour initiation in vivo in an age-dependent fashion.
Aarts M, Georgilis A, Beniazza M, et al., 2017, Coupling shRNA screens with single-cell RNA-Seq identifies a dual role for mTOR in reprogramming-induced senescence, Genes and Development, Vol: 31, Pages: 2085-2098, ISSN: 0890-9369
Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A. We developed an innovative approach that integrates single-cell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates. Our data unveiled regulation of senescence as a novel way by which mechanistic target of rapamycin (mTOR) influences reprogramming. On one hand, mTOR inhibition blunts the induction of cyclin-dependent kinase (CDK) inhibitors (CDKIs), including p16INK4a, p21CIP1, and p15INK4b, preventing OSKM-induced senescence. On the other hand, inhibition of mTOR blunts the senescence-associated secretory phenotype (SASP), which itself favors reprogramming. These contrasting actions contribute to explain the complex effect that mTOR has on reprogramming. Overall, our study highlights the advantage of combining functional screens with scRNA-seq to accelerate the discovery of pathways controlling complex phenotypes.
McHugh D, Gil J, 2017, Senescence and aging – causes, consequences, and therapeutic avenues, Journal of Cell Biology, Vol: 217, Pages: 65-77, ISSN: 0021-9525
Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Although we are far from understanding the biological basis of aging, research suggests that targeting the aging process itself could ameliorate many age-related pathologies. Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome. Senescence plays roles in normal development, maintains tissue homeostasis, and limits tumor progression. However, senescence has also been implicated as a major cause of age-related disease. In this regard, recent experimental evidence has shown that the genetic or pharmacological ablation of senescent cells extends life span and improves health span. Here, we review the cellular and molecular links between cellular senescence and aging and discuss the novel therapeutic avenues that this connection opens.
Young HL, Rowling EJ, Bugatti M, et al., 2017, An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition, Journal of Experimental Medicine, Vol: 214, Pages: 1691-1710, ISSN: 1540-9538
Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands. Fibroblasts require IL-1β to produce CXCR2 ligands, and loss of host IL-1R signaling in vivo reduces melanoma growth. In tumors from patients on treatment, signaling from inflammatory niches is amplified in the presence of MAPK inhibitors. Signaling from inflammatory niches counteracts combined BRAF/MEK (MAPK/extracellular signal–regulated kinase kinase) inhibitor treatment, and consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer drug tolerance toward BRAF and MEK inhibitors early during treatment
Mellone M, Hanley CJ, Thirdborough S, et al., 2016, Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis, Aging, Vol: 9, Pages: 114-132, ISSN: 1945-4589
Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two.
Wong CL, Innes AJ, Ma B, et al., Differential Expression of Genes Associated with Oncogene-Induced Senescence and Senescence Associated Secretory Phenotype in the Absence of Differential Expression of High Molecular Risk Genes and Genes Associated with JAK-STAT Pathway in Sorted Cells of Patients with Polycythemia Vera and Primary Myelofibrosis, 59th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH)/Symposium on the Basic Science of Hemostasis and Thrombosis, Publisher: American Society of Hematology, Pages: 4283-4283, ISSN: 0006-4971
guerrero a, Gil J, 2016, HMGB2 holds the key to the senescence-associated secretory phenotype, Journal of Cell Biology, Vol: 215, Pages: 297-299, ISSN: 1540-8140
The senescence-associated secretory phenotype (SASP) isahallmark of senescencewithimportantphysiologicalimpact, but how it is established is unclear. In this issue, Aird and colleagues(2016. J Cell Biol.xx-xx) describe how chromatin-bound HMGB2 fine-tunesSASP expressionby avoiding heterochromatin spreading.
Tordella L, Khan S, Hohmeyer A, et al., 2016, SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer, Genes & Development, Vol: 30, Pages: 2187-2198-2187-2198, ISSN: 1549-5477
Oncogene-induced senescence (OIS) is a potent tumour suppressor mechanism. Toidentify senescence regulators relevant to cancer, we screened an shRNA librarytargeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe howknockdown of the SWI/SNF component ARID1B prevents OIS and cooperates withRAS to induce liver tumours. ARID1B controls p16INK4a and p21CIP1a transcription butalso regulates DNA damage, oxidative stress and p53 induction, suggesting thatSWI/SNF uses additional mechanisms to regulate senescence. To systematicallyidentify SWI/SNF targets regulating senescence, we carried out a focused shRNAscreen. We discovered several new senescence regulators including ENTPD7, anenzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damageand senescence. Importantly, expression of ENTPD7 or inhibition of nucleotidesynthesis in ARID1B-depleted cells results in re-establishment of senescence. Ourresults identify novel mechanisms by which epigenetic regulators can affect tumorprogression and suggest that pro-senescence therapies could be employed againstSWI/SNF-mutated cancers.
Georgilis A, Gil J, 2016, Controlling secretion to limit chemoresistance, Genes & Development, Vol: 30, Pages: 1791-1792, ISSN: 1549-5477
The tumor microenvironment influences cancer progression and therapy outcome bymechanisms not yet fully understood. In this issue, Bent et al. (2016) show howchemotherapy causes endothelial senescence. Interestingly, senescent endothelial cells donot mount a typical senescence-associated secretory phenotype but instead acutely secreteIL-6, promoting chemoresistance. This study unveils a physiological switch involvingPI3K/AKT/mTOR signaling that restrains the senescence secretory responses to limit thedetrimental consequences of persistent inflammation.
Gil J, Herranz N, 2016, Mitochondria and senescence: new actors for an old play, EMBO Journal, Vol: 35, Pages: 701-702, ISSN: 0261-4189
Mitochondrial dysfunction has been linked to both cellular senescence and ageing. Despite the relationship, it is still unclear whether mitochondria have a causal role in senescence. In this issue of The EMBO Journal, Correia-Melo et al (2016) combine targeted depletion of mitochondria with impairment of their biogenesis to demonstrate that decreased numbers of mitochondria impair the senescence response. Their results suggest that targeting mitochondria could reduce the detrimental effects of senescence during ageing.
Gallage S, Gil J, 2016, Mitochondrial Dysfunction Meets Senescence, TRENDS IN BIOCHEMICAL SCIENCES, Vol: 41, Pages: 207-209, ISSN: 0968-0004
Apps JR, Jani N, Gonzalez-Meljem JM, et al., 2016, Clusters of Nuclear Beta-Catenin Accumulating Cells Form Secretory Hubs in Adamantinomatous Craniopharyngioma, 205th Meeting of the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY-BLACKWELL, Pages: S5-S5, ISSN: 0022-3417
Gil J, Rodriguez T, 2016, Cancer: The Transforming Power of Cell Competition, CURRENT BIOLOGY, Vol: 26, Pages: R164-R166, ISSN: 0960-9822
Gil J, Withers DJ, 2016, Ageing: out with the old, Nature, Vol: 530, Pages: 164-165, ISSN: 0028-0836
The selective elimination of cells that have adopted an irreversible, senescent state has now been shown to extend the lifespan of mice and to ameliorate some age-related disease processes.
Herranz N, Gallage S, Gil J, 2015, TORn about SASP regulation, CELL CYCLE, Vol: 14, Pages: 3771-3772, ISSN: 1538-4101
Esposito MT, Zhao L, Fung TK, et al., 2015, 7Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors, NATURE MEDICINE, Vol: 21, Pages: 1481-+, ISSN: 1078-8956
Adrados I, Larrasa-Alonso J, Galarreta A, et al., 2015, The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes., Oncogene, Vol: 35, Pages: 3485-3494, ISSN: 1476-5594
Cellular senescence is an antiproliferative response with essential functions in tumor suppression and tissue homeostasis. Here we show that SIX1, a member of the SIX family of homeobox transcriptional factors, is a novel repressor of senescence. Our data show that SIX1 is specifically downregulated in fibroblasts upon oncogenic stress and other pro-senescence stimuli, as well as in senescent skin premalignant lesions. Silencing of SIX1 in human fibroblasts suffices to trigger senescence, which is mediated by p16INK4A and lacks a canonical senescence-associated secretory phenotype. Interestingly, SIX1-associated senescence is further characterized by the expression of a set of development and differentiation-related genes that significantly overlap with genes associated with SIX1 in organogenesis or human tumors, and show coincident regulation in oncogene-induced senescence. Mechanistically, we show that gene regulation by SIX1 during senescence is mediated, at least in part, by cooperation with Polycomb repressive complexes. In summary, our results identify SIX1, a key development regulator altered in human tumors, as a critical repressor of cellular senescence, providing a novel connection between senescence, differentiation and tumorigenesis.
Herranz N, Gallage S, Mellone M, et al., 2015, Erratum: mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype., Nat Cell Biol, Vol: 17
O'Loghlen A, Brookes S, Martin N, et al., 2015, CBX7 and miR-9 are part of an autoregulatory loop controlling p16(INK) (4a)., Aging Cell, Vol: 14, Pages: 1113-1121, ISSN: 1474-9726
Polycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR-9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR-9-1 and miR-9-2 as part of a regulatory negative feedback loop. The miR-9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin-dependent kinase inhibitor (CDKI) p16(INK) (4a) during senescence. The ability of the miR-9 family to regulate senescence could have implications for understanding the role of miR-9 in cancer and aging.
Lin M-L, Patel H, Remenyi J, et al., 2015, Expression profiling of nuclear receptors in breast cancer identifies TLX as a mediator of growth and invasion in triple-negative breast cancer, Oncotarget, Vol: 6, Pages: 21685-21703, ISSN: 1949-2553
he Nuclear Receptor (NR) superfamily of transcription factors comprises 48 members, several of which have been implicated in breast cancer. Most important is estrogen receptor-α (ERα), which is a key therapeutic target. ERα action is facilitated by co-operativity with other NR and there is evidence that ERα function may be recapitulated by other NRs in ERα-negative breast cancer. In order to examine the inter-relationships between nuclear receptors, and to obtain evidence for previously unsuspected roles for any NRs, we undertook quantitative RT-PCR and bioinformatics analysis to examine their expression in breast cancer. While most NRs were expressed, bioinformatic analyses differentiated tumours into distinct prognostic groups that were validated by analyzing public microarray data sets. Although ERα and progesterone receptor were dominant in distinguishing prognostic groups, other NR strengthened these groups. Clustering analysis identified several family members with potential importance in breast cancer. Specifically, RORγ is identified as being co-expressed with ERα, whilst several NRs are preferentially expressed in ERα-negative disease, with TLX expression being prognostic in this subtype. Functional studies demonstrated the importance of TLX in regulating growth and invasion in ERα-negative breast cancer cells.
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