Evolution of transmissible cancers and genetics of host resistance

简介:

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.