125 results found
Guerrero A, Innes AJ, Roux P-F, et al., 2022, 3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice, Nature Aging
Bousset L, Gil J, 2022, Targeting senescence as an anti-cancer therapy, Molecular Oncology, 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.
Gil J, Bernard D, Martínez D, et al., 2022, Author Correction: Polycomb CBX7 has a unifying role in cellular lifespan., Nat Cell Biol, Vol: 24
Gil J, Kerai P, Lleonart M, et al., 2022, Editor's Note: Immortalization of Primary Human Prostate Epithelial Cells by c-Myc., Cancer Res, Vol: 82
Olona A, Hateley C, Guerrero A, et 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.
Sweeney M, Cook SA, Gil J, 2022, Therapeutic opportunities for senolysis in cardiovascular disease, FEBS JOURNAL, ISSN: 1742-464X
Gallage S, Ali A, Barragan Avila JE, et 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
Reen V, Gil J, 2021, Clearing stressed cells., Science, Vol: 374, Pages: 534-535
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Prasanna PG, Citrin DE, Hildesheim J, et 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.
Innes A, Sun B, Wagner V, et 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.
Chen J, Sivan U, Tan SL, et 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.
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.
Neeb A, Herranz N, Arce-Gallego S, et 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.
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.
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.
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.
Martínez-Zamudio RI, Roux P-F, Américo NLF de Freitas J, et 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.
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.
Calimport SRG, Bentley BL, Stewart CE, et al., 2020, The inherent challenges of classifying senescence-Response., Science, Vol: 368, Pages: 595-596, ISSN: 0036-8075
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.
Guerrero A, Guiho R, Herranz N, et 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>
Calimport SRG, Bentley BL, Stewart CE, et 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.
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.
Senescence is a cellular stress response that results in the stable arrest of old, damaged or pre-neoplastic cells. Oncogene-induced senescence is tumour suppressive but can also exacerbate tumorigenesis through the secretion of proinflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed ‘senolytics’, have proved beneficial in animal models of many age-associated diseases. In the present study, we show that the cardiac glycoside ouabain is a senolytic agent with broad activity. Senescent cells are sensitized to ouabain-induced apoptosis, a process mediated in part by induction of the proapoptotic Bcl-2 family protein NOXA. We demonstrate that cardiac glycosides synergize with anti-cancer drugs to kill tumour cells and eliminate senescent cells that accumulate after irradiation or in old mice. Ouabain also eliminates senescent pre-neoplastic cells. The findings of the present study suggest that cardiac glycosides may be effective anti-cancer drugs by acting through multiple mechanisms. Given the broad range of senescent cells targeted by cardiac glycosides, their use against age-related diseases warrants further exploration.
Gil J, 2019, Cellular senescence causes ageing, Nature Reviews Molecular Cell Biology, Vol: 20, Pages: 388-388, 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.
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