دورية أكاديمية
أعرض في EDS

Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer.

التفاصيل البيبلوغرافية
العنوان: Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer.
المؤلفون: Ruscetti M; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Morris JP 4th; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Mezzadra R; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Russell J; Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Leibold J; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Romesser PB; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Simon J; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Kulick A; Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Ho YJ; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Fennell M; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Li J; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Norgard RJ; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Wilkinson JE; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA., Alonso-Curbelo D; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Sridharan R; Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, Cornell University, New York, NY 10065, USA., Heller DA; Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, Cornell University, New York, NY 10065, USA., de Stanchina E; Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Stanger BZ; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Sherr CJ; Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Lowe SW; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: lowes@mskcc.org.
المصدر: Cell [Cell] 2020 Apr 16; Vol. 181 (2), pp. 424-441.e21. Date of Electronic Publication: 2020 Mar 31.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE
أسماء مطبوعة: Publication: Cambridge, Ma : Cell Press
Original Publication: Cambridge, MIT Press.
مواضيع طبية MeSH: Aging/*physiology , Carcinoma, Pancreatic Ductal/*pathology , Vascular Remodeling/*physiology, Animals ; CD8-Positive T-Lymphocytes/immunology ; Carcinoma, Pancreatic Ductal/microbiology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase 6/metabolism ; Gene Expression Regulation, Neoplastic/genetics ; Genes, ras/genetics ; Humans ; Immunotherapy/methods ; MAP Kinase Signaling System/physiology ; Mice ; Pancreatic Neoplasms/pathology ; Retinoblastoma Protein/immunology ; Signal Transduction/genetics ; Tumor Microenvironment ; Vascular Remodeling/genetics
مستخلص: KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8 + T cells into otherwise immunologically "cold" tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.
Competing Interests: Declaration of Interests P.B.R. is a consultant for EMD Serono. D.A.H. is a cofounder of LipidSense, Inc., a cofounder and officer with equity interest in Goldilocks Therapeutics Inc., and a member of the scientific advisory board of Concarlo Holdings, LLC. B.Z.S. is an advisor to iTeos Therapeutics and receives research funding from Boehringer Ingelheim. S.W.L. is a founder and scientific advisory board member of Blueprint Medicines, ORIC Pharmaceuticals, and Geras Bio and received an award and honorarium from Eli Lilly and Company. M.R., J.P.M., R.M., J. Leibold, C.J.S., and S.W.L. have filed a U.S. patent application (Ser. No. 62/694,519) related to this work.
(Copyright © 2020. Published by Elsevier Inc.)
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معلومات مُعتمدة: U54 OD020355 United States OD NIH HHS; T32 CA062948 United States CA NCI NIH HHS; K99 CA241110 United States CA NCI NIH HHS; United States HHMI Howard Hughes Medical Institute; P30 CA008748 United States CA NCI NIH HHS; R01 CA215719 United States CA NCI NIH HHS; P01 CA013106 United States CA NCI NIH HHS; K12 CA184746 United States CA NCI NIH HHS; R01 CA194321 United States CA NCI NIH HHS; R01 CA229803 United States CA NCI NIH HHS; P01 CA129243 United States CA NCI NIH HHS; F31 CA232665 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: T cells; chemotherapy resistance; endothelial cell activation; immunotherapy; pancreatic cancer; senescence; senescence-associated secretory phenotype; targeted therapy; tumor microenvironment; vascular biology
المشرفين على المادة: 0 (Retinoblastoma Protein)
EC 2.7.11.22 (CDK4 protein, human)
EC 2.7.11.22 (CDK6 protein, human)
EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
EC 2.7.11.22 (Cyclin-Dependent Kinase 6)
تواريخ الأحداث: Date Created: 20200403 Date Completed: 20201123 Latest Revision: 20220211
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC7278897
DOI: 10.1016/j.cell.2020.03.008
PMID: 32234521
قاعدة البيانات: MEDLINE
الوصف
تدمد:1097-4172
DOI:10.1016/j.cell.2020.03.008