Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.
Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.
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Notch1突变驱动正常食管上皮克隆扩增，但损害肿瘤生长。
DOI：
10.1038/s41588-022-01280-z
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发表时间：
2023-03
期刊：
影响因子：
30.8
通讯作者：
Jones, Philip H. H.
中科院分区：
文献类型：
--
作者：
Abby, Emilie;Dentro, Stefan C. C.;Hall, Michael W. J.;Fowler, Joanna C. C.;Ong, Swee Hoe;Sood, Roshan;Herms, Albert;Piedrafita, Gabriel;Abnizova, Irina;Siebel, Christian W. W.;Gerstung, Moritz;Hall, Benjamin A. A.;Jones, Philip H. H.
NOTCH1突变克隆占据了中年人正常食管的大部分，但在食管癌中相对罕见，这表明NOTCH1突变驱动克隆扩张，但阻碍癌变。在这里，我们测试这个假设。对衰老人食管中的NOTCH1突变克隆进行测序揭示了阻断NOTCH1信号传导的频繁双等位基因突变。在小鼠食管中，杂合Notch1突变赋予了相对于野生型细胞的竞争优势，第二等位基因的缺失增强了这种效应。广泛的Notch1丢失改变转录，但对上皮结构和细胞动力学的影响很小。在致癌模型中，Notch1突变在肿瘤中的发生率低于正常上皮。Notch1的缺失减少了肿瘤生长，这是抗NOTCH1抗体治疗所重现的效果。Notch1无效肿瘤显示增殖减少。我们得出结论，Notch1突变在正常上皮细胞是有益的，因为野生型Notch1有利于肿瘤的扩大。阻断NOTCH1可能在预防食管鳞状细胞癌方面具有治疗潜力。Notch1突变对小鼠食管正常细胞和肿瘤细胞的克隆生长具有相反的影响。在鳞状食管肿瘤发生的小鼠模型中，Notch1阻断减少了癌前肿瘤的生长，这表明它可能是该疾病的有效预防策略。
NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer. Notch1 mutations have opposing effects on clonal growth in normal and tumor cells of the mouse esophagus. In a mouse model of squamous esophageal tumorigenesis, Notch1 blockade reduced premalignant tumor growth, suggesting that it might be an effective prevention strategy for the disease.
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影响因子：
3.2
作者：
Chiang MY;Radojcic V;Maillard I
通讯作者：
Maillard I
DOI：
10.1126/science.aau3879
发表时间：
2018-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Martincorena I;Fowler JC;Wabik A;Lawson ARJ;Abascal F;Hall MWJ;Cagan A;Murai K;Mahbubani K;Stratton MR;Fitzgerald RC;Handford PA;Campbell PJ;Saeb-Parsy K;Jones PH
通讯作者：
Jones PH
影响因子：
64.8
作者：
Cancer Genome Atlas Research Network;Analysis Working Group: Asan University;BC Cancer Agency;Brigham and Women’s Hospital;Broad Institute;Brown University;Case Western Reserve University;Dana-Farber Cancer Institute;Duke University;Greater Poland Cancer Centre;Harvard Medical School;Institute for Systems Biology;KU Leuven;Mayo Clinic;Memorial Sloan Kettering Cancer Center;National Cancer Institute;Nationwide Children’s Hospital;Stanford University;University of Alabama;University of Michigan;University of North Carolina;University of Pittsburgh;University of Rochester;University of Southern California;University of Texas MD Anderson Cancer Center;University of Washington;Van Andel Research Institute;Vanderbilt University;Washington University;Genome Sequencing Center: Broad Institute;Washington University in St. Louis;Genome Characterization Centers: BC Cancer Agency;Broad Institute;Harvard Medical School;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University;University of North Carolina;University of Southern California Epigenome Center;University of Texas MD Anderson Cancer Center;Van Andel Research Institute;Genome Data Analysis Centers: Broad Institute;Brown University:;Harvard Medical School;Institute for Systems Biology;Memorial Sloan Kettering Cancer Center;University of California Santa Cruz;University of Texas MD Anderson Cancer Center;Biospecimen Core Resource: International Genomics Consortium;Research Institute at Nationwide Children’s Hospital;Tissue Source Sites: Analytic Biologic Services;Asan Medical Center;Asterand Bioscience;Barretos Cancer Hospital;BioreclamationIVT;Botkin Municipal Clinic;Chonnam National University Medical School;Christiana Care Health System;Cureline;Duke University;Emory University;Erasmus University;Indiana University School of Medicine;Institute of Oncology of Moldova;International Genomics Consortium;Invidumed;Israelitisches Krankenhaus Hamburg;Keimyung University School of Medicine;Memorial Sloan Kettering Cancer Center;National Cancer Center Goyang;Ontario Tumour Bank;Peter MacCallum Cancer Centre;Pusan National University Medical School;Ribeirão Preto Medical School;St. Joseph’s Hospital &Medical Center;St. Petersburg Academic University;Tayside Tissue Bank;University of Dundee;University of Kansas Medical Center;University of Michigan;University of North Carolina at Chapel Hill;University of Pittsburgh School of Medicine;University of Texas MD Anderson Cancer Center;Disease Working Group: Duke University;Memorial Sloan Kettering Cancer Center;National Cancer Institute;University of Texas MD Anderson Cancer Center;Yonsei University College of Medicine;Data Coordination Center: CSRA Inc.;Project Team: National Institutes of Health
通讯作者：
Project Team: National Institutes of Health
影响因子：
11.8
作者：
Kovall RA;Gebelein B;Sprinzak D;Kopan R
通讯作者：
Kopan R
影响因子：
3.3
作者：
Lubin, Daniel J.;Mick, Rosemarie;Furth, Emma E.
通讯作者：
Furth, Emma E.