89 results found
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 Dev, Vol: 31, Pages: 2085-2098
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.
Mario Gonzalez-Meljem J, Haston S, Carreno G, et al., 2017, Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma., Nat Commun, Vol: 8
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.
McHugh D, Gil J, 2017, Senescence and aging: Causes, consequences, and therapeutic avenues., J Cell Biol
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., J Exp Med, Vol: 214, Pages: 1691-1710
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, ISSN: 0950-9232
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
Gallage S, Gil J, 2016, Mitochondrial Dysfunction Meets Senescence, TRENDS IN BIOCHEMICAL SCIENCES, Vol: 41, Pages: 207-209, ISSN: 0968-0004
Georgilis A, Gil J, 2016, Controlling secretion to limit chemoresistance, GENES & DEVELOPMENT, Vol: 30, Pages: 1791-1792, ISSN: 0890-9369
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
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 JOURNAL, Vol: 35, Pages: 701-702, ISSN: 0261-4189
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
Wong CL, Innes A, Ma B, et al., 2016, 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, 58th Annual Meeting and Exposition of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
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(INK4a), AGING CELL, Vol: 14, Pages: 1113-1121, ISSN: 1474-9718
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, Feraud O, Markossian S, et al., 2015, Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance, NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723
Gallage S, Gil J, 2014, Primary cilia and senescence: A sensitive issue, CELL CYCLE, Vol: 13, Pages: 2653-2654, ISSN: 1538-4101
Gil J, O'Loghlen A, 2014, PRC1 complex diversity: where is it taking us?, TRENDS IN CELL BIOLOGY, Vol: 24, Pages: 632-641, ISSN: 0962-8924
Martin N, Beach D, Gill J, 2014, Ageing as developmental decay: insights from p16(INK4a), TRENDS IN MOLECULAR MEDICINE, Vol: 20, Pages: 667-674, ISSN: 1471-4914
Santos J, Gil J, 2014, TRIM28/KAP1 regulates senescence, IMMUNOLOGY LETTERS, Vol: 162, Pages: 281-289, ISSN: 0165-2478
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, ISSN: 1949-2553
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
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