83 results found
Young HL, Rowling EJ, Bugatti M, et al., 2017, An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition., J Exp Med
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.
Adrados I, Larrasa-Alonso J, Galarreta A, et al., 2016, The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes., Oncogene, Vol: 35, Pages: 3485-3494
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.
Gallage S, Gil J, 2016, Mitochondrial Dysfunction Meets Senescence., Trends Biochem Sci, Vol: 41, Pages: 207-209, ISSN: 0968-0004
Cellular senescence and mitochondrial dysfunction are hallmarks of ageing, but until now their relationship has not been clear. Recent work by Wiley et al. shows that mitochondrial defects can cause a distinct senescence phenotype termed MiDAS (mitochondrial dysfunction-associated senescence). MiDAS has a specific secretome that is able to drive some of the aging phenotypes. These findings suggest novel therapeutic opportunities for treating age-related pathologies.
Georgilis A, Gil J, 2016, Controlling secretion to limit chemoresistance., Genes Dev, Vol: 30, Pages: 1791-1792
The tumor microenvironment influences cancer progression and therapy outcome by mechanisms not yet fully understood. In this issue of Genes & Development, Bent and colleagues (pp. 1811-1821) show how chemotherapy causes endothelial senescence. Interestingly, senescent endothelial cells do not mount a typical senescence-associated secretory phenotype but instead acutely secrete IL-6, promoting chemoresistance. This study unveils a physiological switch involving PI3K/AKT/mTOR signaling that restrains the senescence secretory responses to limit the detrimental consequences of persistent inflammation.
Gil J, Rodriguez T, 2016, Cancer: The Transforming Power of Cell Competition., Curr Biol, Vol: 26, Pages: R164-R166
The tumour-host microenvironment plays key roles in cancer, but the mechanisms involved are not fully understood. Two new studies provide insight into this problem by showing that through cell competition, a fitness-sensing process that usually eliminates defective cells, pre-cancerous lesions signal the death of surrounding tissue that in turn promotes their neoplastic transformation.
Gil J, Withers DJ, 2016, AGEING Out with the old, NATURE, Vol: 530, Pages: 164-165, ISSN: 0028-0836
Guerrero A, Gil J, 2016, HMGB2 holds the key to the senescence-associated secretory phenotype., J Cell Biol, Vol: 215, Pages: 297-299
The senescence-associated secretory phenotype (SASP) is a hallmark of senescence with an important physiological impact, but how it is established is unclear. In this issue, Aird et al. (2016. J. Cell Biol. https://doi.org/10.1083/jcb.201608026) describe how chromatin-bound HMGB2 fine tunes SASP expression by avoiding heterochromatin spreading.
Herranz N, Gil J, 2016, Mitochondria and senescence: new actors for an old play., EMBO J, Vol: 35, Pages: 701-702
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.
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 (Albany NY), Vol: 9, Pages: 114-132
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. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.
Tordella L, Khan S, Hohmeyer A, et al., 2016, SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer, GENES & DEVELOPMENT, Vol: 30, Pages: 2187-2198, ISSN: 0890-9369
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
Guerrero A, Iglesias C, Raguz S, et al., 2015, The cerebral cavernous malformation 3 gene is necessary for senescence induction, AGING CELL, Vol: 14, Pages: 274-283, ISSN: 1474-9718
Herranz N, Gallage S, Gil J, 2015, TORn about SASP regulation., Cell Cycle, Vol: 14, Pages: 3771-3772
Herranz N, Gallage S, Mellone M, et al., 2015, mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype, NATURE CELL BIOLOGY, Vol: 17, Pages: 1205-+, ISSN: 1465-7392
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
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
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
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(INK4a) 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.
O'Loghlen A, Martin N, Krusche B, et al., 2015, The nuclear receptor NR2E1/TLX controls senescence, ONCOGENE, Vol: 34, Pages: 4069-4077, ISSN: 0950-9232
Ozmadenci D, Féraud O, Markossian S, et al., 2015, Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance., Nat Commun, Vol: 6
The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. The use of the transcription factors Oct4, Sox2, Klf4 and c-Myc for reprogramming is extensively documented, but comparatively little is known about soluble molecules promoting reprogramming. Here we identify the secreted cue Netrin-1 and its receptor DCC, described for their respective survival/death functions in normal and oncogenic contexts, as reprogramming modulators. In various somatic cells, we found that reprogramming is accompanied by a transient transcriptional repression of Netrin-1 mediated by an Mbd3/Mta1/Chd4-containing NuRD complex. Mechanistically, Netrin-1 imbalance induces apoptosis mediated by the receptor DCC in a p53-independent manner. Correction of the Netrin-1/DCC equilibrium constrains apoptosis and improves reprogramming efficiency. Our work also sheds light on Netrin-1's function in protecting embryonic stem cells from apoptosis mediated by its receptor UNC5b, and shows that the treatment with recombinant Netrin-1 improves the generation of mouse and human iPS cells.
Gallage S, Gil J, 2014, Primary cilia and senescence: a sensitive issue., Cell Cycle, Vol: 13, Pages: 2653-2654
Gil J, O'Loghlen A, 2014, PRC1 complex diversity: where is it taking us?, Trends Cell Biol, Vol: 24, Pages: 632-641
Polycomb group proteins (PcGs) are essential epigenetic regulators that play key roles in development, pluripotency, senescence, and cancer. Recent reports have found that the composition of mammalian Polycomb repressive complex 1 (PRC1) is far more varied than previously thought. PRC1 diversity largely depends on the presence of CBX proteins, dividing them into canonical and non-canonical, the existence of redundant subunits, and different binding affinities and/or regulation. However, there is no clear insight into how many functional PRC1 complexes exist and what the biological relevance is for such diversification. In this review we focus on mammalian PRC1 and discuss the mechanisms by which canonical and non-canonical PRC1 are recruited to chromatin, their role in normal development and disease, and emerging evidence for PRC1 as a transcriptional activator.
Martin N, Beach D, Gil J, 2014, Ageing as developmental decay: insights from p16(INK4a.)., Trends Mol Med, Vol: 20, Pages: 667-674
The p16(INK4a) cell cycle regulator is one of the best ageing biomarkers because it is suppressed in early embryogenesis and progressively induced during ageing. p16(INK4a) plays a crucial role in key cell fate decisions which contribute to ageing, such as cellular senescence and stem cell dynamics. Detailed examination of the pathways regulating p16(INK4a) expression has revealed an overlap with those regulating early development. We present the hypothesis that ageing might be primarily driven by gradual functional decay of developmental pathways. To support this, we summarise the role of p16(INK4a) in ageing and our current knowledge on p16(INK4a) regulation. The developmental decay hypothesis implies that the much-evidenced damage associated with all aspects of ageing might be secondary to such decay.
Santos J, Gil J, 2014, TRIM28/KAP1 regulates senescence., Immunol Lett, Vol: 162, Pages: 281-289
Senescence is a highly stable cell cycle arrest which limits the replication of cells with damaged genomes. The senescence program is activated during aging or in response to insults like DNA damage or oncogenic signaling. Upon induction of senescence, cells undergo profound changes on their transcription program, chromatin organization, and they secrete a complex mixture of mainly pro-inflammatory components termed the senescence-associated secretory phenotype (SASP). The SASP mediates multiple effects, including reinforcing senescence and activating immune surveillance responses. Given the important role that senescence has in aging, cancer and other pathologies, identifying mechanisms regulating senescence has therapeutic potential. Here we describe a role for TRIM28 (also known as KRAB-associated protein 1, KAP1) on mediating oncogene-induced senescence (OIS). TRIM28 accumulates during OIS becoming phosphorylated on serine 824. To investigate the role of TRIM28, we knocked down its expression and observed that the depletion of TRIM28 partially prevented cell arrest during OIS. While induction of p53 and p21 during OIS, was not affected by TRIM28 depletion, p16(INK4a) induction was partially prevented. Finally, we observed that the induction of IL8, IL6 and other SASP components were strongly suppressed upon TRIM28 depletion. In conclusion, the above-described results show that TRIM28 regulates senescence and affects the induction of the senescence-associated secretory phenotype.
Vizioli MG, Santos J, Pilotti S, et al., 2014, Oncogenic RAS-induced senescence in human primary thyrocytes: molecular effectors and inflammatory secretome involved., Oncotarget, Vol: 5, Pages: 8270-8283
Oncogene-induced senescence (OIS) is a robust and sustained antiproliferative response to oncogenic stress and constitutes an efficient barrier to tumour progression. We have recently proposed that OIS may be involved in the pathogenesis of thyroid carcinoma by restraining tumour progression as well as the transition of well differentiated to more aggressive variants. Here, an OIS inducible model was established and used for dissecting the molecular mechanisms and players regulating senescence in human primary thyrocytes. We show that oncogenic RAS induces senescence in thyrocytes as judged by changes in cell morphology, activation of p16INK4a and p53/p21CIP1 tumour suppressor pathways, senescence-associated β-galactosidase (SA-β-Gal) activity, and induction of proinflammatory components including IL-8 and its receptor CXCR2. Using RNA interference (RNAi) we demonstrate that p16INK4a is necessary for the onset of senescence in primary thyrocytes as its depletion rescues RAS-induced senescence. Furthermore, we found that IL-8/CXCR2 network reinforces the growth arrest triggered by oncogenic RAS, as its abrogation is enough to resume proliferation. Importantly, we observed that CXCR2 expression coexists with OIS markers in thyroid tumour samples, suggesting that CXCR2 contributes to senescence, thus limiting thyroid tumour progression.
Warboys CM, de Luca A, Amini N, et al., 2014, Disturbed Flow Promotes Endothelial Senescence via a p53-Dependent Pathway, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 34, Pages: 985-995, ISSN: 1079-5642
Acosta JC, Banito A, Wuestefeld T, et al., 2013, A complex secretory program orchestrated by the inflammasome controls paracrine senescence, NATURE CELL BIOLOGY, Vol: 15, Pages: 978-U221, ISSN: 1465-7392
Acosta JC, Snijders AP, Gil J, 2013, Unbiased characterization of the senescence-associated secretome using SILAC-based quantitative proteomics., Methods Mol Biol, Vol: 965, Pages: 175-184
Approaches based on the combination of mass spectrometry (MS) and quantitative methods have the potential to generate unbiased, thorough proteomic catalogues. In particular, stable isotope labeling with amino acid in cell culture (SILAC) has been used to perform highly accurate quantitative comparisons between the proteomes of different cell lines, treatments, or even animal models. Here, we describe how we have taken advantage of SILAC-based quantitative proteomics and inducible cell systems of oncogene-induced senescence to make an unbiased characterization of the senescence-associated secretome. This approach could be used to analyze the effect of diverse molecules on the senescence secretome or to catalogue unrelated secretomes.
Gómez-Cabello D, Adrados I, Gamarra D, et al., 2013, DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts., Aging Cell, Vol: 12, Pages: 923-931
The regulation of gene expression by microRNAs (miRNAs) is critical for normal development and physiology. Conversely, miRNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual miRNAs or dysregulation of miRNA synthesis. Here, we have investigated the impact of global disruption of miRNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of DGCR8, an essential mediator of the synthesis of canonical miRNAs. We find that the inactivation of DGCR8 in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by DGCR8 loss is accompanied by the upregulation of the cell-cycle inhibitor p21CIP1. We further show that a subset of senescence-associated miRNAs with the potential to target p21CIP1 is downregulated during DGCR8-mediated senescence. Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical microRNAs results in cell-cycle arrest and cellular senescence in primary fibroblasts mediated by specific miRNAs, and thus identify global miRNA disruption as a novel senescence trigger.
Marqués-Torrejón MÁ, Porlan E, Banito A, et al., 2013, Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression., Cell Stem Cell, Vol: 12, Pages: 88-100
In the adult brain, continual neurogenesis of olfactory neurons is sustained by the existence of neural stem cells (NSCs) in the subependymal niche. Elimination of the cyclin-dependent kinase inhibitor 1A (p21) leads to premature exhaustion of the subependymal NSC pool, suggesting a relationship between cell cycle control and long-term self-renewal, but the molecular mechanisms underlying NSC maintenance by p21 remain unexplored. Here we identify a function of p21 in the direct regulation of the expression of pluripotency factor Sox2, a key regulator of the specification and maintenance of neural progenitors. We observe that p21 directly binds a Sox2 enhancer and negatively regulates Sox2 expression in NSCs. Augmented levels of Sox2 in p21 null cells induce replicative stress and a DNA damage response that leads to cell growth arrest mediated by increased levels of p19(Arf) and p53. Our results show a regulation of NSC expansion driven by a p21/Sox2/p53 axis.
Martin N, Popov N, Aguilo F, et al., 2013, Interplay between Homeobox proteins and Polycomb repressive complexes in p16(INK4a) regulation, EMBO JOURNAL, Vol: 32, Pages: 982-995, ISSN: 0261-4189
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