MONDAY, MARCH 22
12:30-1:30 pm Conference Registration
1:30-1:40 Welcoming Remarks from Conference Director
Julia Boguslavsky, Executive Director, Conferences, Cambridge Healthtech Institute
1:40-1:45 Chairperson’s Opening Remarks
1:45-2:10 Title to be Announced
Carlo M. Croce, M.D., Professor, Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University
2:10-2:35 Title to be Announced
Philip N. Tsichlis, M.D., Professor, Hematology and Oncology, Tufts University School of Medicine; Executive Director, Molecular Oncology Research Institute, Tufts Medical Center
2:35-3:00 Genetic Dissection of the OncomiR-1 Cluster in Mice
Andrea Ventura, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center
MiR-17~92 (OncomiR-1) has emerged as the prototypical oncogenic microRNA cluster in humans and mice. It encodes six distinct miRNAs that can be grouped into four “seed families” (miR17/20, miR-18, miR-19a/b and miR-92). We have previously reported the generation and characterization of mice carrying a targeted deletion of the entire cluster. Homozygous mutant mice are significantly smaller than their wild type counterpart, die soon after birth and display a complex array of defects involving heart lungs and lymphocyte development. One limitation of such an analysis is that these results were obtained by deleting the entire miR-17~92 locus. As such, little is known with respect to the relative role of each of the six microRNAs encoded by miR-17~92. We will discuss the results of two parallel lines of investigation that our laboratory is undertaking to address this important issue: a) We have carried out a systematic genetic analysis by creating an allelic series of knock-in mice, each lacking only one of the four “seed families” encoded by miR-17~92. To our knowledge, this is the first time such an analysis is being carried out in mammals; b) We have used a conditional miR-17~92 knockout allele to determine the role of this cluster in Myc-induced B cell lymphomas. By using this approach we show that endogenous miR-17~92 is required in lymphoma to suppress apoptosis via the concerted action on a number of genes and that this effect is largely, if not exclusively attributable to the miR-19 seed family.
3:00-3:30 Networking Refreshment Break
3:30-3:55 Molecular Epidemiology and Functional Analysis of microRNAs in Human Cancers
Yong Zhu, Ph.D., Associate Professor, Department of Epidemiology and Public Health, Yale School of Medicine
We first performed a genetic association analysis by screening genetic variants in all human microRNA genes in our population-based cancer case-control studies. CpG islands upstream of the identified microRNAs were also analyzed in an epigenetic association study. We further delivered expression vectors containing either wild-type or mutant precursors of the identified microRNAs into cultured cells, and performed a variety of functional analyses and pathway-based network analysis. Our findings suggest that microRNAs may play a role in both breast tumorigenesis and lymphogenesis, and both genetic and epigenetic variants in microRNA genes could serve as novel biomarkers for cancer susceptibility.
3:55-4:20 From Worms to Humans: Understanding the Role of miRNAs in Cancer Progression
Aurora Esquela-Kerscher, Ph.D., Assistant Professor, Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School
miRNAs regulate important developmental events and are often misexpressed in human cancers, but little is known regarding how these molecules contribute to tumor formation. Our laboratory uses a combination of nematode and mammalian model systems to functionally characterize miRNAs and determine the role these factors play in controlling processes related to cellular growth and differentiation. The let-7 miRNA family is postulated to function as tumor suppressor genes in tissues such as the lung by regulating the oncogenes RAS, MYC, and HMGA2 as well as several cell cycle progression genes. We will present recent findings regarding our work on the role of let-7 together with other miRNA families in directing cancer progression pathways during development and in human tissues, particularly of urothelial origin.
4:20-4:45 Epigenetics and microRNAs in Cancer
Muller Fabbri, M.D., Research Scientist, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center
Epigenetics refers to heritable changes in gene expression that are not associated with concomitant alterations in the DNA sequence. Reversible DNA methylation and histone modifications are the hallmarks of epigenetic gene regulation. microRNAs undergo the same epigenetic regulatory mechanisms of all other genes, but can also regulate effectors of the epigenetic machinery. This intertwined regulatory network between the miRNome and the epigenome is responsible for the aberrant expression of microRNAs observed in several human malignancies, and contributes to human cancerogenesis.
4:45-5:45 Opening Reception with Exhibit and Poster Viewing