Evolution of transmissible cancers and genetics of host resistance

摘要： 癌症不是单一的事件。它继续进化，因为IS繁殖，通过宿主传播，并逃避其 宿主的基本识别机制。我们发现了一个反转录转座子，Steamer，在一个白血病样细胞中扩增 软壳文蛤中的疾病。通过对蒸汽反转录转座子mtDNA整合位点的研究 SNPs和多态微卫星，我发现这种疾病是通过水平传播的 白血病细胞本身，起着传染性癌症的作用，我们发现这是一种广泛存在的 在多个双壳类中的现象。根据我在博士指导下进行的初步调查。 哥伦比亚大学的斯蒂芬·戈夫，我提议研究可传播癌症的进化和 反转录元件Steamer在疾病发展中的作用以及M。 无节幼虫白血病与宿主抗药性的发展。这项研究将建立在我之前在 逆转录病毒学和癌症生物学，因为我将过渡到独立的学术研究职位 开发这种癌症系统作为白血病的独特模型。这将在三个独立的阶段完成，但是 相互关联的目标：(1)研究推动癌症进化的突变和选择压力 包括蒸汽反转录转座子的作用，(2)决定癌细胞的途径和机制 以及(3)确定癌细胞植入/排斥的宿主基因决定因素。这个独一无二的 无脊椎动物癌症模型将使我们了解更多关于癌症进化和逆转录因子在 癌症，并研究白血病的获得性和自我/非我识别的基本机制。

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.