Imperial College London

ProfessorJesusGil

Faculty of MedicineInstitute of Clinical Sciences

Professor of Cell Proliferation
 
 
 
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Contact

 

+44 (0)20 3313 8263jesus.gil

 
 
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Location

 

ICTEM room 230ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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132 results found

Duran I, Pombo J, Sun B, Gallage S, Kudo H, McHugh D, Bousset L, Avila JEB, Forlano R, Manousou P, Heikenwalder M, Withers DJ, Vernia S, Goldin RD, Gil Jet al., 2024, Detection of senescence using machine learning algorithms based on nuclear features, Nature Communications, Pages: 1-20, ISSN: 2041-1723

Cellular senescence is a stress response with broad pathophysiological implications. Senotherapies can induce senescence to treat cancer or eliminate senescent cells to ameliorate ageing and age-related pathologies. However, the success of senotherapies is limited by the lack of reliable ways to identify senescence. Here, we use nuclear morphology features of senescent cells to devise machine-learning classifiers that accurately predict senescence induced by diverse stressors in different cell types and tissues. As a proof-of-principle, we use these senescence classifiers to characterise senolytics and to screen for drugs that selectively induce senescence in cancer cells but not normal cells. Moreover, a tissue senescence score served to assess the efficacy of senolytic drugs and identified senescence in mouse models of liver cancer initiation, ageing, and fibrosis, and in patients with fatty liver disease. Thus, senescence classifiers can help to detect pathophysiological senescence and to discover and validate potential senotherapies.

Journal article

McHugh D, Sun B, Gutierrez-Muñoz C, Hernández-González F, Mellone M, Guiho R, Duran I, Pombo J, Pietrocola F, Birch J, Kallemeijn WW, Khadayate S, Dharmalingam G, Vernia S, Tate EW, Martínez-Barbera JP, Withers DJ, Thomas GJ, Serrano M, Gil Jet al., 2023, COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells, Nature Cell Biology, Vol: 25, Pages: 1804-1820, ISSN: 1465-7392

Drugs that selectively kill senescent cells (senolytics) improve the outcomes of cancer, fibrosis and age-related diseases. Despite their potential, our knowledge of the molecular pathways that affect the survival of senescent cells is limited. To discover senolytic targets, we performed RNAi screens and identified coatomer complex I (COPI) vesicle formation as a liability of senescent cells. Genetic or pharmacological inhibition of COPI results in Golgi dispersal, dysfunctional autophagy, and unfolded protein response-dependent apoptosis of senescent cells, and knockdown of COPI subunits improves the outcomes of cancer and fibrosis in mouse models. Drugs targeting COPI have poor pharmacological properties, but we find that N-myristoyltransferase inhibitors (NMTi) phenocopy COPI inhibition and are potent senolytics. NMTi selectively eliminated senescent cells and improved outcomes in models of cancer and non-alcoholic steatohepatitis. Our results suggest that senescent cells rely on a hyperactive secretory apparatus and that inhibiting trafficking kills senescent cells with the potential to treat various senescence-associated diseases.

Journal article

Gil J, 2023, The challenge of identifying senescent cells, Nature Cell Biology, Vol: 25, Pages: 1554-1556, ISSN: 1465-7392

Journal article

Guo C, Sharp A, Gurel B, Crespo M, Figueiredo I, Jain S, Vogl U, Rekowski J, Rouhifard M, Gallagher L, Yuan W, Carreira S, Chandran K, Paschalis A, Colombo I, Stathis A, Bertan C, Seed G, Goodall J, Raynaud F, Ruddle R, Swales KE, Malia J, Bogdan D, Tiu C, Caldwell R, Aversa C, Ferreira A, Neeb A, Tunariu N, Westaby D, Carmichael J, Fenor de la Maza MDLD, Yap C, Matthews R, Badham H, Prout T, Turner A, Parmar M, Tovey H, Riisnaes R, Flohr P, Gil J, Waugh D, Decordova S, Schlag A, Calì B, Alimonti A, de Bono JSet al., 2023, Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance, Nature, Vol: 623, Pages: 1053-1061, ISSN: 0028-0836

Inflammation is a hallmark of cancer1. In cancer patients, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio (NLR), associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives prostate cancer progression in humans remain unclear. Herein we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients. We show that higher blood NLR reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species including myeloid chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel androgen receptor signaling inhibitor (ARSI) resistance, and if inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with ARSI-resistant mCRPC. This combination was well tolerated without dose-limiting toxicity and decreased circulating neutrophils, reduced intratumor CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration, and imparted durable clinical benefit with biochemical and radiological responses in a subset of mCRPC patients. This study provides the first clinical evidence that senescence-associated myeloid inflammation can fuel mCRPC progression and resistance to AR blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.

Journal article

White MEH, Gil J, Tate EW, 2023, Proteome-wide structural analysis identifies warhead- and coverage-specific biases in cysteine-focused chemoproteomics, Cell Chemical Biology, Vol: 30, Pages: 828-838.e4, ISSN: 2451-9456

Covalent drug discovery has undergone a resurgence over the past two decades and reactive cysteine profiling has emerged in parallel as a platform for ligand discovery through on- and off-target profiling; however, the scope of this approach has not been fully explored at the whole-proteome level. We combined AlphaFold2-predicted side-chain accessibilities for >95% of the human proteome with a meta-analysis of eighteen public cysteine profiling datasets, totaling 44,187 unique cysteine residues, revealing accessibility biases in sampled cysteines primarily dictated by warhead chemistry. Analysis of >3.5 million cysteine-fragment interactions further showed that hit elaboration and optimization drives increased bias against buried cysteine residues. Based on these data, we suggest that current profiling approaches cover a small proportion of potential ligandable cysteine residues and propose future directions for increasing coverage, focusing on high-priority residues and depth. All analysis and produced resources are freely available and extendable to other reactive amino acids.

Journal article

Haston S, Gonzalez-Gualda E, Morsil S, Ge J, Reen V, Calderwood A, Moutsopoulos I, Panousopoulos L, Deletc P, Carreno G, Guiho R, Manshaei S, Gonzalez-Meljem JM, Lim HY, Simpson DJ, Birch J, Pallikonda HA, Chandra T, Macias D, Doherty GJ, Rassl DM, Rintoul RC, Signore M, Mohorianu I, Akbar AN, Gil J, Munoz-Espín D, Martinez-Barbera JPet al., 2023, Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer, Cancer Cell, Vol: 41, Pages: 1242-1260.e6, ISSN: 1535-6108

Accumulation of senescent cells in the tumour microenvironment can drive tumourigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are thepredominant senescent cell types in murine KRAS-driven lung tumours. Through single cell transcriptomics, we identify a population of tumour-associated macrophages that express a unique array of pro-tumourigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant reduction in tumour burden and increased survival in KRAS-driven lungcancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung premalignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progressionof lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies.

Journal article

Gil J, DAmbrosio M, 2023, Reshaping of the tumor microenvironment by cellular senescence: an opportunity for senotherapies, Developmental Cell, Vol: 58, Pages: 1007-1021, ISSN: 1534-5807

Cellular senescence is a stress response associated with aging and disease, including cancer.Senescent cells undergo a stable cell cycle arrest, change in morphology, metabolicreprogramming and produce a bioactive secretome termed the senescence-associatedsecretory phenotype (SASP). In cancer, senescence is an important barrier to tumorprogression. Induction of senescence in preneoplastic cells limits cancer initiation and manycancer therapies act in part by inducing senescence in cancer cells. Paradoxically, senescentcells lingering in the tumor microenvironment (TME) can contribute to tumor progression,metastasis and therapy resistance. In this Review we discuss the different types of senescentcells present in the TME and how these senescent cells and their SASP reshape the TME,affect immune responses and influence cancer progression. Furthermore, we will highlight theimportance of senotherapies, including senolytic drugs that eliminate senescent cells andimpede tumor progression and metastasis by restoring anti-tumor immune responses andinfluencing the TME.

Journal article

Isima N, Gil J, 2023, Spurious transcription may be a hallmark of aging, Nature Aging, Vol: 3, Pages: 374-375, ISSN: 2662-8465

Epigenetic changes are a driver of senescence and occur during aging. A study in Nature Aging shows how chromatin-mediated loss of transcription fidelity, previously shown in yeast and worms, also occurs in mammalian cells and could constitute a new hallmark of senescence and aging.

Journal article

Gil J, 2023, 3-Deazaadenosine keeps senescence at bay, Aging, Vol: 15, Pages: 2369-2370, ISSN: 1945-4589

Journal article

Sweeney M, Cook SA, Gil J, 2023, Therapeutic opportunities for senolysis in cardiovascular disease, The Federation of European Biochemical Societies (FEBS) Journal, Vol: 290, Pages: 1235-1255, ISSN: 1742-464X

Cellular senescence within the cardiovascular system has, until recently, been understudied and unappreciated as a factor in the development of age-related cardiovascular diseases such as heart failure, myocardial infarction and atherosclerosis. This is in part due to challenges with defining senescence within post-mitotic cells such as cardiomyocytes. However, recent evidence has demonstrated senescent-like changes, including a senescence-associated secretory phenotype (SASP), in cardiomyocytes in response to ageing and cell stress. Other replicating cells, including fibroblasts and vascular smooth muscle cells, within the cardiovascular system have also been shown to undergo senescence and contribute to disease pathogenesis. These findings coupled with the emergence of senolytic therapies, to target and eliminate senescent cells, have provided fascinating new avenues for management of several age-related cardiovascular diseases with high prevalence. In this review, we discuss the role of senescent cells within the cardiovascular system and highlight the contribution of senescence cells to common cardiovascular diseases. We discuss the emerging role for senolytics in cardiovascular disease management while highlighting important aspects of senescence biology which must be clarified before the potential of senolytics can be fully realized.

Journal article

Born E, Lipskaia L, Breau M, Houssaini A, Beaulieu DP, Marcos E, Pierre R, Do Cruzeiro M, Lefevre M, Derumeaux G, Bulavin DV, Delcroix M, Quarck R, Reen V, Gil J, Bernard D, Flaman J-M, Adnot S, Abid Set al., 2023, Eliminating senescent cells can promote pulmonary hypertension development and progression, Circulation, Vol: 147, Pages: 650-666, ISSN: 0009-7322

BACKGROUND: Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the role of SCs in animal pulmonary hypertension models. METHODS: We investigated senescence (p16, p21) and DNA damage (γ-H2AX, 53BP1) markers in patients with pulmonary arterial hypertension and murine models. We monitored p16 activation by luminescence imaging in p16-luciferase (p16LUC/+) knock-in mice. SC clearance was obtained by a suicide gene (p16 promoter-driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]), and p16 inactivation in p16LUC/LUC mice. We investigated pulmonary hypertension in mice exposed to normoxia, chronic hypoxia, or hypoxia+Sugen, mice overexpressing the serotonin transporter (SM22-5-HTT+), and rats given monocrotaline. RESULTS: Patients with pulmonary arterial hypertension compared with controls exhibited high lung p16, p21, and γ-H2AX protein levels, with abundant vascular cells costained for p16, γ-H2AX, and 53BP1. Hypoxia increased thoracic bioluminescence in p16LUC/+ mice. In wild-type mice, hypoxia increased lung levels of senescence and DNA-damage markers, senescence-associated secretory phenotype components, and p16 staining of pulmonary endothelial cells (P-ECs, 30% of lung SCs in normoxia), and pulmonary artery smooth muscle cells. SC elimination by suicide gene or ABT263 increased the right ventricular systolic pressure and hypertrophy index, increased vessel remodeling (higher dividing proliferating cell nuclear antigen-stained vascular cell counts during both normoxia and hypoxia), and markedly decreased lung P-ECs. Pulmonary hemodynamic alterations and lung P-EC loss occurred in older p16LUC/LUC mice, wild-type mice exposed to Sugen or hypoxia+Sugen, and SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI, compared with releva

Journal article

Bousset L, Gil J, 2022, Targeting senescence as an anti-cancer therapy, Molecular Oncology, Vol: 16, Pages: 3855-3880, ISSN: 1574-7891

Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age-related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis. In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anti-cancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. "One-two punch" therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment. Future challenges of "one -two punch" approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy.

Journal article

Guerrero A, Innes AJ, Roux P-F, Buisman SC, Jung J, Ortet L, Moiseeva V, Wagner V, Robinson L, Ausema A, Potapova A, Perdiguero E, Weersing E, Aarts M, Martin N, Wuestefeld T, Muñoz-Cánoves P, de Haan G, Bischof O, Gil Jet al., 2022, 3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice, Nature Aging, Vol: 2, Pages: 851-866, ISSN: 2662-8465

Cellular senescence is a stable type of cell cycle arrest triggered by different stresses. As such, senescence drives age-related diseases and curbs cellular replicative potential. Here, we show that 3-deazaadenosine (3DA), an S-adenosyl homocysteinase inhibitor, alleviates replicative and oncogene-induced senescence. 3DA-treated senescent cells showed reduced global histone H3 lysine 36 trimethylation, an epigenetic modification that marks the bodies of actively transcribed genes. By integrating transcriptome and epigenome data, we demonstrate that 3DA treatment affects key factors of the senescence transcriptional program. Notably, 3DA treatment alleviated senescence and increased the proliferative and regenerative potential of muscle stem cells from very old mice in vitro and in vivo. Moreover, ex vivo 3DA treatment was sufficient to enhance the engraftment of human umbilical cord blood cells in immunocompromised mice. Together, our results identify 3DA as a promising drug enhancing the efficiency of cellular therapies by restraining senescence.

Journal article

Olona A, Hateley C, Guerrero A, Ko J-H, Johnson MR, Anand PK, Thomas D, Gil J, Behmoaras Jet al., 2022, Cardiac glycosides cause cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis, British Journal of Pharmacology, Vol: 179, Pages: 1874-1886, ISSN: 0007-1188

Background and purpose: Cardiac glycosides (CGs) inhibit the Na+,K+‐ATPase and are widely prescribed medicines for chronic heart failure and cardiac arrhythmias. Recently, CGs have been described to induce inflammasome activation and pyroptosis in human macrophages, suggesting a cytotoxicity that remains to be elucidated in tissues.Experimental approach: To determine the cell type specificity of CG‐mediated cytotoxicity, we used human primary monocyte‐derived macrophages (hMDMs) and non‐adherent peripheral blood cells isolated from healthy donors. Omental white adipose tissue (WAT) and stromal vascular fraction (SVF)‐derived pre‐adipocytes and adipocytes were isolated from obese patients undergoing bariatric surgery. All these primary cells/tissues were treated with nanomolar concentrations of ouabain (50nM, 100nM and 500nM) to investigate its degree of cytotoxicity and mechanisms leading to cell death. In WAT, we further explored the consequences of ouabain‐mediated cytotoxicity by measuring insulin sensitivity, adipose tissue function and extracellular matrix (ECM) deposition ex vivo.Key results: The ouabain‐induced cell death is through pyroptosis and apoptosis, and more efficient in hMDMs compared to non‐adherent PBMC populations. This selective cytotoxicity is dependent on K+ flux, as ouabain causes an intracellular depletion of K+, while inducing accumulation of Na+ and Ca2+ levels. Consistently, the cell‐death caused by these ion imbalances can be rescued by addition of potassium chloride in hMDMs. Remarkably, when WAT explants from obese patients are cultured with nanomolar concentrations of ouabain, this causes depletion of macrophages, down‐regulation of type VI collagen levels, and amelioration of insulin sensitivity ex vivo.Conclusions and implications: These results suggest that the usage of nanomolar concentration of CGs can be an attractive therapeutic avenue in metabolic syndrome characterised by pathogenic infiltration and activation of macrophages.

Journal article

Gallage S, Ali A, Barragan Avila JE, Herebian D, Karimi MM, Irvine EE, McHugh D, Schneider AT, Vucur M, Keitel V, Gil J, Withers DJ, Luedde T, Heikenwalder Met al., 2021, Spontaneous cholemia in C57BL/6 mice predisposes to liver cancer in NASH, Cellular and Molecular Gastroenterology and Hepatology, Vol: 13, Pages: 875-878, ISSN: 2352-345X

Journal article

Prasanna PG, Citrin DE, Hildesheim J, Ahmed MM, Venkatachalam S, Riscuta G, Xi D, Zheng G, van Deursen J, Goronzy J, Kron SJ, Anscher MS, Sharpless NE, Campisi J, Brown SL, Niedernhofer LJ, O'Loghlen A, Georgakilas AG, Paris F, Gius D, Gewirtz DA, Schmitt CA, Abazeed ME, Kirkland JL, Richmond A, Romesser PB, Lowe SW, Gil J, Mendonca MS, Burma S, Zhou D, Coleman CNet al., 2021, Therapy-induced senescence: opportunities to improve anti-cancer therapy, Journal of the National Cancer Institute, Vol: 113, Pages: 1285-1298, ISSN: 0027-8874

Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.

Journal article

Innes A, Sun B, Wagner V, Brookes S, McHugh D, Pombo J, Porreca RM, Dharmalingam G, Vernia S, Zuber J, Vannier J-B, García-Escudero R, Gil Jet al., 2021, XPO7 is a tumor suppressor regulating p21CIP1-dependent senescence, Genes and Development, Vol: 35, Pages: 379-391, ISSN: 0890-9369

Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an impaired induction of the cyclin dependent kinase inhibitor p21CIP1 during OIS. Deletion of XPO7 correlates with poorer overall survival in several cancer types. Moreover, depletion of XPO7 alleviated OIS and increased tumor formation in a mouse model of liver cancer. Our results suggest that XPO7 is a novel tumor suppressor that regulates p21CIP1 expression to control senescence and tumorigenesis.

Journal article

Chen J, Sivan U, Tan SL, Lippo L, De Angelis J, Labella R, Singh A, Chatzis A, Cheuk S, Medhghalchi M, Gil J, Hollander G, Marsden BD, Williams R, Ramasamy SK, Kusumbe APet al., 2021, High-resolution 3D imaging uncovers organ-specific vascular control of tissue aging, Science Advances, Vol: 7, Pages: 1-17, ISSN: 2375-2548

Blood vessels provide supportive microenvironments for maintaining tissue functions. Age-associated vascular changes and their relation to tissue aging and pathology are poorly understood. Here, we perform 3D imaging of young and aging vascular beds. Multiple organs in mice and humans demonstrate an age-dependent decline in vessel density and pericyte numbers, while highly remodeling tissues such as skin preserve the vasculature. Vascular attrition precedes the appearance of cellular hallmarks of aging such as senescence. Endothelial VEGFR2 loss-of-function mice demonstrate that vascular perturbations are sufficient to stimulate cellular changes coupled with aging. Age-associated tissue-specific molecular changes in the endothelium drive vascular loss and dictate pericyte to fibroblast differentiation. Lineage tracing of perivascular cells with inducible PDGFRβ and NG2 Cre mouse lines demonstrated that increased pericyte to fibroblast differentiation distinguishes injury-induced organ fibrosis and zymosan-induced arthritis. To spur further discoveries, we provide a freely available resource with 3D vascular and tissue maps.

Journal article

Behmoaras J, Gil J, 2021, Similarities and interplay between senescent cells and macrophages, The Journal of Cell Biology, Vol: 220, ISSN: 0021-9525

Senescence is a cellular program that prevents the replication of old, damaged, or cancerous cells. Senescent cells become growth arrested and undergo changes in their morphology, chromatin organization, and metabolism, and produce a bioactive secretome. This secretome, the senescence-associated secretory phenotype (SASP), mediates many of the pathophysiological effects associated with senescent cells, for example, recruiting and activating immune cells such as macrophages. The relation between senescent cells and macrophages is intriguing: senescent cells recruit macrophages, can induce them to undergo senescence, or can influence their polarization. Senescent cells and macrophages share multiple phenotypic characteristics; both have a high secretory status, increased lysosome numbers, or the ability to activate the inflammasome. Senescent cells accumulate during aging and disease, and killing them results in widespread benefits. Here we discuss similarities between senescent cells and macrophages and interpret the latest developments in macrophage biology to understand the molecular mechanisms of cellular senescence. We describe evidence and effects of senescence in macrophages and speculate on the ontogeny of the senescent-like state in macrophages. Finally, we examine the macrophage–senescent cell interplay and its impact on macrophage effector functions during inflammatory conditions and in the tumor microenvironment.

Journal article

Neeb A, Herranz N, Arce-Gallego S, Miranda S, Buroni L, Yuan W, Athie A, Casals T, Carmichael J, Rodrigues DN, Gurel B, Rescigno P, Rekowski J, Welti J, Riisnaes R, Gil V, Ning J, Wagner V, Casanova-Salas I, Cordoba S, Castro N, Fenor de la Maza MD, Seed G, Chandran K, Ferreira A, Figueiredo I, Bertan C, Bianchini D, Aversa C, Paschalis A, Gonzalez M, Morales-Barrera R, Suarez C, Carles J, Swain A, Sharp A, Gil J, Serra V, Lord C, Carreira S, Mateo J, de Bono JSet al., 2021, Advanced prostate cancer with ATM Loss: PARP and ATR inhibitors, European Urology, Vol: 79, Pages: 200-211, ISSN: 0302-2838

BACKGROUND: Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond. OBJECTIVE: To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset. DESIGN, SETTING, AND PARTICIPANTS: We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays. In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: ATM expression by IHC was correlated with clinical outcome using Kaplan-Meier curves and log-rank test; sensitivity to different drug combinations was assessed in the preclinical models. RESULTS AND LIMITATIONS: Overall, we detected ATM IHC loss in 68/631 (11%) PC patients in at least one biopsy, with synchronous and metachronous intrapatient heterogeneity; 46/71 (65%) biopsies with ATM loss had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transitions, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP inhibition; superior antitumour activity was seen with combined PARP and ATR inhibition in these models. CONCLUSIONS: ATM loss in PC is not always detected by targeted NGS, associates with genomic instability, and is most sensitive to combined ATR and PARP inhibition. PATIENT SUMMARY: Of aggressive prostate cancers, 10% lose the DNA repair gene ATM; this loss may identify a distinct prostate cancer subtype that is most sensitive to the combination of oral drugs targeting PARP and ATR.

Journal article

Birch J, Gil J, 2020, Senescence and the SASP: many therapeutic avenues, Genes and Development, Vol: 34, Pages: 1565-1576, ISSN: 0890-9369

Cellular senescence is a stress response that elicits a permanent cell cycle arrest and triggers profound phenotypic changes such as the production of a bioactive secretome, referred to as the senescence-associated secretory phenotype (SASP). Acute senescence induction protects against cancer and limits fibrosis, but lingering senescent cells drive age-related disorders. Thus, targeting senescent cells to delay ageing and limit dysfunction, known as ‘senotherapy’, is gaining momentum. While drugs that selectively kill senescent cells, termed ‘senolytics’, are a major focus, SASP-centered approaches are emerging as alternatives to target senescence-associated diseases. Here, we summarise the regulation and functions of the SASP and highlight the therapeutic potential of SASP modulation as complimentary, or an alternative to, current senolytic approaches.

Journal article

de Bono JS, Guo C, Gurel B, De Marzo AM, Sfanos KS, Mani RS, Gil J, Drake CG, Alimonti Aet al., 2020, Prostate carcinogenesis: inflammatory storms, Nature Reviews Cancer, Vol: 20, Pages: 455-469, ISSN: 1474-175X

Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury and an altered microbiome being causally implicated. Intra-prostatic inflammatory cell recruitment and expansion can ultimately promote DNA double-strand breaks and androgen receptor activation in prostate epithelial cells. The activation of the senescence-associated secretory phenotype fuels further 'inflammatory storms', with free radicals leading to further DNA damage. This drives the overexpression of DNA repair and tumour suppressor genes, rendering these genes susceptible to mutagenic insults, with carcinogenesis accelerated by germline DNA repair gene defects. We provide updates on recent advances in elucidating prostate carcinogenesis and explore novel therapeutic and prevention strategies harnessing these discoveries.

Journal article

Wagner V, Gil J, 2020, T cells engineered to target senescence, Nature, Vol: 583, Pages: 37-38, ISSN: 0028-0836

Senescence is a hallmark of cellular ageing and contributes to many diseases. A new method enabling immune cells to target senescent cells might offer improved therapeutic options.

Journal article

Martínez-Zamudio RI, Roux P-F, Américo NLF de Freitas J, Robinson L, Doré G, Sun B, Belenki D, Milanovic M, Herbig U, Schmitt CA, Gil J, Bischof Oet al., 2020, AP-1 imprints a reversible transcriptional program of senescent cells, Nature Cell Biology, Vol: 22, Pages: 842-855, ISSN: 1465-7392

Senescent cells affect many physiological and pathophysiological processes. While select genetic and epigenetic elements for senescence induction have been identified, the dynamics, epigenetic mechanisms and regulatory networks defining senescence competence, induction and maintenance remain poorly understood, precluding the deliberate therapeutic targeting of senescence for health benefits. Here, we examined the possibility that the epigenetic state of enhancers determines senescent cell fate. We explored this by generating time-resolved transcriptomes and epigenome profiles during oncogenic RAS-induced senescence and validating central findings in different cell biology and disease models of senescence. Through integrative analysis and functional validation, we reveal links between enhancer chromatin, transcription factor recruitment and senescence competence. We demonstrate that activator protein 1 (AP-1) ‘pioneers’ the senescence enhancer landscape and defines the organizational principles of the transcription factor network that drives the transcriptional programme of senescent cells. Together, our findings enabled us to manipulate the senescence phenotype with potential therapeutic implications.

Journal article

Gil J, 2020, Senescence as a therapeutically relevant response to CDK4/6 inhibitors, Oncogene, Vol: 39, Pages: 5165-5176, ISSN: 0950-9232

Cyclin-dependent kinases 4 and 6 (CDK4/6) phosphorylate and inhibit retinoblastoma (RB) family proteins. Hyperphosphorylated RB releases E2F transcription factors, activating a transcriptional program that initiates S phase. Due to the critical role that this pathway has in regulating cell cycle progression, inhibiting CDK4/6 is an attractive therapeutic strategy. Indeed, CDK4/6 inhibitors in combination with antiestrogens produce a significant benefit in patients with ER+/HER2− breast cancer. Clinical trials are currently investigating if the use of CDK4/6 inhibitors alone or in combination can be extended to other cancer types. Inhibition of CDK4/6 can result in different cell fates such as quiescence, senescence, or apoptosis. Senescence is a stress response that can be induced by stimuli that include oncogenic activation, chemotherapy, irradiation, and targeted therapies such as CDK4/6 inhibitors. Senescent cells undergo a stable cell cycle arrest and produce a bioactive secretome that remodels their microenvironment and engages the immune system. In this review, we analyze the therapeutic relevance of senescence induction by CDK4/6 inhibitors. We also discuss how different therapies, including checkpoint inhibitors and drugs targeting MEK or PI3K, can be used in combination with CDK4/6 inhibitors to reinforce or exploit senescence. Recently, a lot of effort has been put into identifying compounds that selectively kill senescent cells (termed senolytics). Thus, sequential treatment with senolytics might be an additional strategy to potentiate the antitumor effects of CDK4/6 inhibitors.

Journal article

Calimport SRG, Bentley BL, Stewart CE, Pawelec G, Scuteri A, Vinciguerra M, Slack C, Chen D, Harries LW, Marchant G, Fleming GA, Conboy M, Antebi A, Small GW, Gil J, Lakatta EG, Richardson A, Rosen C, Nikolich K, Wyss-Coray T, Steinman L, Montine T, de Magalhães JP, Campisi J, Church Get al., 2020, The inherent challenges of classifying senescence-Response., Science, Vol: 368, Pages: 595-596, ISSN: 0036-8075

Journal article

Birch J, Gil J, 2020, Blunting senescence boosts liver regeneration, Genes and Development, Vol: 34, Pages: 463-464, ISSN: 0890-9369

The mammalian liver possesses a unique capacity for regeneration. However, this regenerative potential declines with age due to unknown mechanisms. In this issue of Genes & Development, Ritschka and colleagues (pp. 489–494). compare liver regeneration upon partial hepatectomy in young and adult mice. Partial hepatectomy causes a transient increase in p21 in a subpopulation of hepatocytes that persists in adult mice. Remarkably, treatment with the BCL-2 family inhibitor ABT-737 blunts p21 expression, enhancing liver regeneration.

Journal article

Guerrero A, Guiho R, Herranz N, Uren A, Withers DJ, Martínez-Barbera JP, Tietze LF, Gil Jet al., 2020, Galactose-modified duocarmycin prodrugs as senolytics, Aging Cell, Vol: 19, Pages: 1-13, ISSN: 1474-9718

Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with diseases, such as cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β-galactosidase this has been exploited as a marker for senescence (senescence-associated β-galactosidase activity). Consequently, we hypothesised that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole body irradiation or doxorubicin treatment of mice. Moreover, taking advantage of a mouse model of human adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD pro-drug result selectively reduced the number of β-catenin-positive preneoplastic senescent cells, what could have therapeutic implications. In summary, the above results show that galactose-modified duocarmycin prodrugs behave as senolytics, suggesting that they could be used to treat a wide range of senescence-related pathologies.</jats:p>

Journal article

Calimport SRG, Bentley BL, Stewart CE, Pawelec G, Scuteri A, Vinciguerra M, Slack C, Chen D, Harries LW, Marchant G, Fleming GA, Conboy M, Antebi A, Small GW, Gil J, Lakatta EG, Richardson A, Rosen C, Nikolich K, Wyss-Coray T, Steinman L, Montine T, de Magalhães JP, Campisi J, Church Get al., 2019, To help aging populations, classify organismal senescence, Science, Vol: 366, Pages: 576-578, ISSN: 0036-8075

Globally, citizens exist for sustained periods in states of aging-related disease and multimorbidity. Given the urgent and unmet clinical, health care, workforce, and economic needs of aging populations, we need interventions and programs that regenerate tissues and organs and prevent and reverse aging-related damage, disease, and frailty (1). In response to these challenges, the World Health Organization (WHO) has called for a comprehensive public-health response within an international legal framework based on human rights law (1). Yet for a clinical trial to be conducted, a disease to be diagnosed, intervention prescribed, and treatment administered; a corresponding disease classification code is needed, adopted nationally from the WHO International Classification of Diseases (ICD). Such classifications and staging are fundamental for health care governance among governments and intergovernmental bodies. We describe a systematic and comprehensive approach to the classification and staging of organismal senescence and aging-related diseases at the organ and tissue levels in order to guide policy and practice and enable appropriate interventions and clinical guidance, systems, resources, and infrastructure.

Journal article

Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, Campisi J, Collado M, Evangelou K, Ferbeyre G, Gil J, Hara E, Krizhanovsky V, Jurk D, Maier AB, Narita M, Niedernhofer L, Passos JF, Robbins PD, Schmitt CA, Sedivy J, Vougas K, von Zglinicki T, Zhou D, Serrano M, Demaria Met al., 2019, Cellular senescence: defining a path forward, Cell, Vol: 179, Pages: 813-827, ISSN: 0092-8674

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Thus, accurate detection of senescent cells, especially in vivo, is essential especially since the field of senotherapeutics is growing rapidly. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendation on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence (SeneQuest, available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.

Journal article

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