Evolution of transmissible cancers and genetics of host resistance

传染性癌症的进化和宿主耐药性的遗传学

• 批准号: 9899956
• 负责人: Michael Jeffrey Metzger
• 金额: $ 19.3万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899956
• 关键词: Animals; Bivalvia; Bromodeoxyuridine; CRISPR/Cas technology; Cancer Biology; Cancer Etiology; Cancer Model; Candidate Disease Gene; Cells; Chromium; Clams; Clinical; Cloning; Collaborations; DNA Transposable Elements; DNA copy number; Development; Diagnosis; Disease; Engraftment; European; Event; Evolution; Experimental Models; Exposure to; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genome; Genomic Segment; Gills; Goals; Graft Rejection; Hemocytes; Hemolymph; Horizontal Disease Transmission; Host resistance; Human; Immune response; Individual; Infiltration; Injections; Integration Host Factors; Invertebrates; Investigation; Kinetics; Lead; Learning; Leukemic Cell; Location; Malignant - descriptor; Malignant Neoplasms; Mentorship; Methods; Microsatellite Repeats; Mitochondrial DNA; Modeling; Morbidity - disease rate; Mussels; Mutation; Neoplasm Metastasis; Neoplasms; Normal Cell; Oncogenes; Oncogenic; Oysters; Play; Population; Positioning Attribute; Predisposition; Process; Proto-Oncogenes; Reporting; Research; Resistance; Retroelements; Retrotransposon; Retroviral Vector; Retrovirology; Role; Route; Sampling; Seawater; Site; Steam; Structure; System; Testing; Training; United States National Institutes of Health; Universities; Variant; base; cancer cell; cancer genetics; feeding; genetic linkage analysis; integration site; leukemia; mortality; mouse model; neoplastic; neoplastic cell; pathogen; pressure; public health relevance; reference genome; tissue culture; transmission process

SUMMARY: Cancer is not a single event. It continues to evolve as is multiplies, spreads through its host, and evades its host’s basic mechanisms of recognition. We identified a retrotransposon, Steamer, amplified in a leukemia-like disease in soft-shell clams. Through investigation of integration sites of the Steamer retrotransposon, mtDNA SNPs, and polymorphic microsatellites, I discovered that the disease is spread by horizontal transmission of leukemic cells themselves, acting as a contagious cancer, and we have found that this is a widespread phenomenon in multiple bivalves. Based on my preliminary investigations while under the mentorship of Dr. Stephen Goff at Columbia University, I propose to investigate the evolution of transmissible cancers and the role of the retroelement, Steamer, in development of the disease as well as the mechanism of transmission of M. arenaria leukemia and the development of host resistance. This research will build on my previous training in retrovirology and cancer biology as I transition into independent academic research position where I will develop this cancer system as a unique model of leukemia. This will be done in three independent, but interconnected aims: (1) Investigate the mutations and selective pressures which drive cancer evolution including the role of the Steamer retrotransposon, (2) determine the route and mechanism of cancer cell transmission, and (3) identify the host genetic determinants of cancer cell engraftment/rejection. This unique invertebrate cancer model will allow us to learn more about cancer evolution and the role of retroelements in cancer, and to investigate leukemia acquisition and fundamental mechanisms of self/nonself recognition.

概括： 癌症不是一个单一的事件，它会不断繁殖、通过宿主传播并逃避它。 我们鉴定了一种逆转录转座子，Steamer，在白血病样细胞中扩增。 通过研究 Steamer 逆转录转座子 mtDNA 的整合位点。 SNPs和多态性微卫星，我发现这种疾病是通过水平传播的 白血病细胞本身，作为一种传染性癌症，我们发现这是一种广泛传播的疾病 基于我在博士的指导下进行的初步调查。 哥伦比亚大学的斯蒂芬·戈夫（Stephen Goff），我提议研究传染性癌症的演变以及 逆转录因子 Steamer 在疾病发展中的作用以及支原体传播机制。 这项研究将建立在我之前的培训基础上。 逆转录病毒学和癌症生物学，当我过渡到独立学术研究职位时，我将 开发这种癌症系统作为白血病的独特模型这将通过三个独立的但完成的。 相互关联的目标：（1）研究驱动癌症进化的突变和选择压力 包括Steamer逆转录转座子的作用，（2）确定癌细胞的途径和机制 (3) 确定癌细胞植入/排斥的宿主遗传决定因素。 无脊椎动物癌症模型将使我们能够更多地了解癌症的进化以及逆转录因子在癌症中的作用 癌症，并研究白血病的获得和自我/非自我识别的基本机制。

项目成果

Prevalence and polymorphism of a mussel transmissible cancer in Europe.

• DOI: 10.1111/mec.16052
• 发表时间: 2022-03
• 期刊: Molecular ecology
• 影响因子: 4.9
• 作者: Hammel M;Simon A;Arbiol C;Villalba A;Burioli EAV;Pépin JF;Lamy JB;Benabdelmouna A;Bernard I;Houssin M;Charrière GM;Destoumieux-Garzon D;Welch JJ;Metzger MJ;Bierne N
• 通讯作者: Bierne N

A single clonal lineage of transmissible cancer identified in two marine mussel species in South America and Europe.

在南美洲和欧洲的两种海洋贻贝物种中发现了传染性癌症的单一克隆谱系。

• DOI: 10.7554/elife.47788
• 发表时间: 2019
• 期刊: eLife
• 影响因子: 7.7
• 作者: Yonemitsu,MarisaA;Giersch,RachaelM;Polo-Prieto,Maria;Hammel,Maurine;Simon,Alexis;Cremonte,Florencia;Avilés,FernandoT;Merino-Véliz,Nicolás;Burioli,ErikaAv;Muttray,AnnetteF;Sherry,James;Reinisch,Carol;Baldwin,SusanA;Goff,Ste
• 通讯作者: Goff,Ste

From the raw bar to the bench: Bivalves as models for human health

• DOI: 10.1016/j.dci.2018.11.020
• 发表时间: 2019-03-01
• 期刊: DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY
• 影响因子: 2.9
• 作者: Robledo，Jose A. Fernandez;Yadavalli，Raghavendra;Metzger，Michael J.
• 通讯作者: Metzger，Michael J.