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The Contribution of Physiological and Accelerated Aging to Cancer Progression Through Senescence-Induced Inflammation

Morales-Valencia, Jorge; David, Gregory
Senescent cells are found to accumulate in aged individuals, as well as in cancer patients that receive chemotherapeutic treatment. Although originally believed to halt cancer progression due to their characteristic growth arrest, senescent cells remain metabolically active and secrete a combination of inflammatory agents, growth factors and proteases, collectively known as the senescence-associated secretory phenotype (SASP). In this review, we discuss the contribution of senescent cells to cancer progression through their ability to alter cancer cells"™ properties and to generate a microenvironment that promotes tumor growth. Furthermore, recent evidence suggests that senescent cells are able resume proliferation and drive cancer relapse, pointing to the use of senolytics and SASP modulators as a potential approach to prevent tumor resurgence following treatment cessation. Thus, a better understanding of the hallmarks of senescence and the impact of the SASP will allow the development of improved targeted therapeutic strategies to leverage vulnerabilities associated with this cellular state.
ISSN: 2234-943x
CID: 5055522

Regulation of the Methylation and Expression Levels of the BMPR2 Gene by SIN3a as a Novel Therapeutic Mechanism in Pulmonary Arterial Hypertension

Bisserier, Malik; Mathiyalagan, Prabhu; Zhang, Shihong; Elmastour, Firas; Dorfmüller, Peter; Humbert, Marc; David, Gregory; Tarzami, Sima; Weber, Thomas; Perros, Frederic; Sassi, Yassine; Sahoo, Susmita; Hadri, Lahouaria
BACKGROUND:Epigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation of the BMPR2 (bone morphogenetic protein receptor type 2) promoter is associated with BMPR2 downregulation and progression of PAH. Here, we investigated for the first time the role of SIN3a (switch-independent 3a), a transcriptional regulator, in the epigenetic mechanisms underlying hypermethylation of BMPR2 in the pathogenesis of PAH. METHODS:We used lung samples from PAH patients and non-PAH controls, preclinical mouse and rat PAH models, and human pulmonary arterial smooth muscle cells. Expression of SIN3a was modulated using a lentiviral vector or a siRNA in vitro and a specific adeno-associated virus serotype 1 or a lentivirus encoding for human SIN3a in vivo. RESULTS:SIN3a is a known transcriptional regulator; however, its role in cardiovascular diseases, especially PAH, is unknown. It is interesting that we detected a dysregulation of SIN3 expression in patients and in rodent models, which is strongly associated with decreased BMPR2 expression. SIN3a is known to regulate epigenetic changes. Therefore, we tested its role in the regulation of BMPR2 and found that BMPR2 is regulated by SIN3a. It is interesting that SIN3a overexpression inhibited human pulmonary arterial smooth muscle cells proliferation and upregulated BMPR2 expression by preventing the methylation of the BMPR2 promoter region. RNA-sequencing analysis suggested that SIN3a downregulated the expression of DNA and histone methyltransferases such as DNMT1 (DNA methyltransferase 1) and EZH2 (enhancer of zeste 2 polycomb repressive complex 2) while promoting the expression of the DNA demethylase TET1 (ten-eleven translocation methylcytosine dioxygenase 1). Mechanistically, SIN3a promoted BMPR2 expression by decreasing CTCF (CCCTC-binding factor) binding to the BMPR2 promoter. Last, we identified intratracheal delivery of adeno-associated virus serotype human SIN3a to be a beneficial therapeutic approach in PAH by attenuating pulmonary vascular and right ventricle remodeling, decreasing right ventricle systolic pressure and mean pulmonary arterial pressure, and restoring BMPR2 expression in rodent models of PAH. CONCLUSIONS:All together, our study unveiled the protective and beneficial role of SIN3a in pulmonary hypertension. We also identified a novel and distinct molecular mechanism by which SIN3a regulates BMPR2 in human pulmonary arterial smooth muscle cells. Our study also identified lung-targeted SIN3a gene therapy using adeno-associated virus serotype 1 as a new promising therapeutic strategy for treating patients with PAH.
PMID: 34078089
ISSN: 1524-4539
CID: 4964772

Breaking Tradition to Bridge Bench and Bedside: Accelerating the MD-PhD-Residency Pathway

Modrek, Aram S; Tanese, Naoko; Placantonakis, Dimitris G; Sulman, Erik P; Rivera, Rafael; Du, Kevin L; Gerber, Naamit K; David, Gregory; Chesler, Mitchell; Philips, Mark R; Cangiarella, Joan
PROBLEM/OBJECTIVE:Physician-scientists are individuals trained in both clinical practice and scientific research. Often, the goal of physician-scientist training is to address pressing questions in biomedical research. The established pathways to formally train such individuals are, mainly, MD-PhD programs and physician-scientist track residencies. Although graduates of these pathways are well equipped to be physician-scientists, numerous factors, including funding and length of training, discourage application to such programs and impede success rates. APPROACH/METHODS:To address some of the pressing challenges in training and retaining burgeoning physician-scientists, New York University Grossman School of Medicine formed the Accelerated MD-PhD-Residency Pathway in 2016. This pathway builds on the previously established accelerated three-year MD pathway to residency at the same institution. The Accelerated MD-PhD-Residency Pathway conditionally accepts MD-PhD trainees to a residency position at the same institution through the National Resident Matching Program. OUTCOMES/RESULTS:Since its inception, 2 students have joined the Accelerated MD-PhD-Residency Pathway, which provides protected research time in their chosen residency. The pathway reduces the time to earn an MD and PhD by one year and reduces the MD training phase to three years, reducing the cost and lowering socioeconomic barriers. Remaining at the same institution for residency allows for the growth of strong research collaborations and mentoring opportunities, which foster success. NEXT STEPS/UNASSIGNED:The authors and institutional leaders plan to increase the number of trainees that are accepted into the Accelerated MD-PhD-Residency Pathway and track the success of these students through residency and into practice to determine if the pathway is meeting its goal of increasing the number of practicing physician-scientists. The authors hope this model can serve as an example to leaders at other institutions who may wish to adopt this pathway for the training of their MD-PhD students.
PMID: 33464738
ISSN: 1938-808x
CID: 4760452

Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis

Yao, Changfu; Guan, Xiangrong; Carraro, Gianni; Parimon, Tanyalak; Liu, Xue; Huang, Guanling; Mulay, Apoorva; Soukiasian, Harmik J; David, Gregory; Weigt, Stephen S; Belperio, John A; Chen, Peter; Jiang, Dianhua; Noble, Paul W; Stripp, Barry R
Rationale: Idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Accelerated aging, loss of epithelial progenitor cell function and/or numbers, and cellular senescence are implicated in the pathogenies of IPF.Objectives: We sought to investigate the role of alveolar type 2 (AT2) cellular senescence in initiation and/or progression of pulmonary fibrosis and therapeutic potential of targeting senescence-related pathways and senescent cells.Methods: Epithelial cells of 9 control donor proximal and distal lung tissues and 11 IPF fibrotic lung tissues were profiled by single-cell RNA sequencing to assesses the contribution of epithelial cells to the senescent cell fraction for IPF. A novel mouse model of conditional AT2 cell senescence was generated to study the role of cellular senescence in pulmonary fibrosis.Measurements and Main Results: We show that AT2 cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of AT2 cells promotes progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation or senescence block fibrogenesis.Conclusions: Senescence of AT2 cells is sufficient to drive progressive pulmonary fibrosis. Early attenuation of senescence-related pathways and elimination of senescent cells are promising therapeutic approaches to prevent pulmonary fibrosis.
PMID: 32991815
ISSN: 1535-4970
CID: 4828542

Softly but surely: A new perspective on transcriptional repression [Editorial]

Plessel, Rebecca L; David, Gregory
PMID: 33410192
ISSN: 1521-1878
CID: 4739672

Pro- and Anti-Tumorigenic Functions of the Senescence-Associated Secretory Phenotype

Lau, Lena; David, Gregory
INTRODUCTION/BACKGROUND:Cellular senescence is a stable form of cell-cycle exit. Though they no longer divide, senescent cells remain metabolically active and secrete a plethora of proteins collectively termed the senescence-associated secretory phenotype (SASP). Although senescence-associated cell-cycle exit likely evolved as an anti-tumor mechanism, the SASP contains both anti- and pro-tumorigenic potential. Areas covered: In this review, we briefly discuss the discovery of senescent cells and its relationship to cancer and aging. We also describe the initiation and regulation of the SASP upon senescence stimulus onset. We focus on both the pro- and anti-tumorigenic properties of the SASP. Finally, we speculate on the potential benefits of therapy-induced senescence combined with selective SASP inhibition for the treatment of cancer. Expert opinion: Further identification and characterization of the SASP factors that are pro-tumorigenic and those that are anti-tumorigenic in specific contexts will be crucial in order to develop personalized therapeutics for the successful treatment of cancer.
PMID: 30616404
ISSN: 1744-7631
CID: 3579812

Uncoupling the senescence-associated secretory phenotype from cell cycle exit via IL-1 inactivation unveils its pro-tumorigenic role

Lau, Lena; Porciuncula, Angelo; Yu, Alex; Iwakura, Yoichiro; David, Gregory
Cellular senescence has emerged as a potent tumor-suppressor mechanism in numerous human neoplasias. Senescent cells secrete a distinct set of factors collectively termed the senescence-associated secretory phenotype (SASP), which has been postulated to carry both pro- and anti-tumorigenic properties depending on tissue context. However, the in vivo effect of the SASP is poorly understood due to the difficulty of studying the SASP independently of other senescence-associated phenotypes. Here, we report that disruption of the IL-1 pathway completely uncouples the SASP from other senescence-associated phenotypes such as cell cycle exit. Transcriptome profiling of IL-1 receptor (IL-1R) - depleted senescent cells indicates that IL-1 controls the late arm of the senescence secretome, which consists of pro-inflammatory cytokines induced by NF-κB. Our data suggest that both interleukin (IL)-1α and IL-1β signal through IL-1R to upregulate the SASP in a cooperative manner. Finally, we show that IL-1α inactivation impairs tumor progression and immune cell infiltration without affecting cell cycle arrest in a mouse model of pancreatic cancer, highlighting the pro-tumorigenic property of the IL-1-dependent SASP in this context. These findings provide novel insight into the therapeutic potential of targeting the IL-1 pathway in inflammatory cancers.
PMID: 30988157
ISSN: 1098-5549
CID: 3810412

NAD+ metabolism governs the proinflammatory senescence-associated secretome

Nacarelli, Timothy; Lau, Lena; Fukumoto, Takeshi; Zundell, Joseph; Fatkhutdinov, Nail; Wu, Shuai; Aird, Katherine M; Iwasaki, Osamu; Kossenkov, Andrew V; Schultz, David; Noma, Ken-Ichi; Baur, Joseph A; Schug, Zachary; Tang, Hsin-Yao; Speicher, David W; David, Gregory; Zhang, Rugang
Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.
PMID: 30778219
ISSN: 1476-4679
CID: 3687802

Prostate-specific loss of UXT promotes cancer progression

Wang, Yu; Schafler, Eric D; Thomas, Phillip A; Ha, Susan; David, Gregory; Adney, Emily; Garabedian, Michael J; Lee, Peng; Logan, Susan K
Ubiquitously-expressed, prefoldin-like chaperone (UXT) also called Androgen Receptor Trapped clone-27 (ART-27) is widely expressed in human tissues. Our previous studies showed that UXT regulates transcription repression including androgen receptor (AR) signaling in prostate cancer. Here we analyzed a tissue microarray consisting of normal prostate, benign prostatic hyperplasia, high grade prostatic intraepithelial neoplasia (HGPIN) and primary prostate cancer cases for UXT protein expression. We found that HGPIN and malignant tumors have significantly decreased UXT expression compared to the normal prostate. Loss of UXT expression in primary prostate cancer is positively associated with high Gleason grade and poor relapse-free survival. We engineered prostate-specific Uxt
PMID: 30774773
ISSN: 1949-2553
CID: 3658372

Impaired Expression of Rearranged Immunoglobulin Genes and Premature p53 Activation Block B Cell Development in BMI1 Null Mice

Cantor, David J; King, Bryan; Blumenberg, Lili; DiMauro, Teresa; Aifantis, Iannis; Koralov, Sergei B; Skok, Jane A; David, Gregory
B cell development is a highly regulated process that requires stepwise rearrangement of immunoglobulin genes to generate a functional B cell receptor (BCR). The polycomb group protein BMI1 is required for B cell development, but its function in developing B cells remains poorly defined. We demonstrate that BMI1 functions in a cell-autonomous manner at two stages during early B cell development. First, loss of BMI1 results in a differentiation block at the pro-B cell to pre-B cell transition due to the inability of BMI1-deficient cells to transcribe newly rearranged Igh genes. Accordingly, introduction of a pre-rearranged Igh allele partially restored B cell development in Bmi1-/- mice. In addition, BMI1 is required to prevent premature p53 signaling, and as a consequence, Bmi1-/- large pre-B cells fail to properly proliferate. Altogether, our results clarify the role of BMI1 in early B cell development and uncover an unexpected function of BMI1 during VDJ recombination.
PMID: 30605667
ISSN: 2211-1247
CID: 3562892