The license could not be verified: License Certificate has expired!
Michael J. Difilippantonio, Ph.D.
National Cancer Institute
Division of Cancer Treatment and Diagnosis
31 Center Drive, Room 3A44
Bethesda, Maryland 20892
Dr. Difilippantonio earned his B.S. at the University of Connecticut in Molecular and Cellular Biology and a Certificate in Cytogenetics from the University of Connecticut School of Allied Health. He subsequently worked as a Clinical Cytogenetic Technologist in the laboratory of Dr. David C. Ward at Yale University in the early days of the Human Genome Project where he acquired proficiency in the emerging field of fluorescence in situ hybridization. He earned his Ph.D. in Genetics from Yale University under the mentorship of Dr. David G. Schatz. Dr. Difilippantonio came to NIH in 1998 as a post-doctoral fellow in the laboratory of Dr. Thomas Ried, initially in the National Human Genome Research Institute and now in the National Cancer Institute. In 2001 Dr. Difilippantonio became a Staff Scientist in the Ried lab where he continued to pursue his interests in colorectal cancer as well as the role of DNA damage repair in tumorigenesis, where he worked closely with collaborator Andre Nussenzweig (NCI). He received the NCI Division of Clinical Sciences Fellowship Advancement Award in 2000, was awarded the Aspen Cancer Conference Young Investigator Award in 2001 and was recognized for his various contributions through receipt of an NCI Performance Award in 2002, 2007, 2008 and 2009. He was Co-Chair of the CCR-Staff Scientist/Staff Clinician Organization from 2005-2006, was the first elected Chair of the NIH-Staff Scientist/Staff Clinician Organization in 2009-2010, and served as the Staff Scientist representative on the NIH Assembly of Scientists (AOS) Council from 2007-2010. Dr. Difilippantonio has been an Associate Editor of the BMC open access journal Molecular Cancer since 2003. In May 2009 he embarked on a detail in the Office of the Director (OD) in the NCI extramural Division of Cancer Treatment and Diagnosis (DCTD). One year later he accepted a position as the Program Manager for Therapeutic and Diagnostic Initiatives (DCTD/OD) where he is responsible for, among other activities, overseeing the Functional Biology Consortium, managing space for the Division, serving as the Division representative on the NCI Health and Safety Committee and to the NCI Risk Assessment Program, and assists in tracking Division funding for extramural grants, NCI Experimental Therapeutics (NExT) Program projects, and SAIC-F laboratory efforts.
Dr. Difilippantonio has had a particular interest in DNA double strand break repair and its role in the generation of chromosome translocations leading to tumor formation. In his position as a Staff Scientist he was intimately involved in a number of different ongoing projects in the lab as well as with collaborators in other NIH institutes and outside universities. Some of the main projects in which he was involved are outlined below. These involved the study of human and mouse models of tumorigenesis using a variety of genomic techniques, including fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), comparative genomic hybridization (CGH), immunocytochemistry (ICC), gene expression profiling (microarrays), quantitative real-time PCR (RT-PCR), epifluorescence and confocal microscopy.
Structural Chromosome Aberrations and Cancer
Tumors are characterized by their inability to maintain the integrity of the genome, either through mutation or rearrangement of genomic sequences. Cells have multiple mechanisms whereby they can repair DNA damage or for those cells in which repair is not possible, induce cell death. The non-homologous end-joining DNA double-strand break repair pathway is one such mechanism and involves the coordinated effort of many different proteins. Of particular importance is the DNA-PK complex consisting of the proteins DNA-PKcs, Ku70 and Ku80. Mice deficient for either of the genes encoding the Ku proteins are particularly sensitive to the DNA damaging effects of ionizing radiation. In previous collaborative studies with Dr. Nussenzweig (NCI), they demonstrated that cells in the developing embryos of these mice have a propensity to develop DNA breaks, chromosome rearrangements and aneuploidy even in the absence of IR. Most of these cells, however, either undergo cell death or senescence, resulting in the runted growth of these mice relative to their normal siblings. Breeding of these mice with mice deficient for the protein p53, which is known to induce cell death, results in mice that develop tumors in the B cell lineage at a very early age. These tumors are characterized by a specific chromosomal rearrangement involving the immunoglobulin heavy chain gene (IgH) and the tumor promoting gene c-myc. Such an IgH - c-myc rearrangement is seen in Burkitt's lymphoma in humans and is believed to result in the misregulated growth characteristic of cancer cells. Further characterization of these tumors revealed that the chromosome translocations were occurring through the process of break-induced replication (BIR). Subsequent amplification of the IgH / c-myc fusion was the result of repeated cycles of breakage-fusion-bridge (BFB) and eventual stabilization of the aberrant chromosome end via telomere capture from another chromosome.
Numerical Chromosome Aberrations and Cancer
The partitioning of genomic material during cell division is critical for maintaining the genomic content of each daughter cell. Centrosomes are one of the primary cellular structures responsible for this process. As such, Dr. Difilippantonio in collaboration with Dr. Ghadimi (University of Gottingen, Germany) investigated defects in these structures and the proteins that regulate them in order to determine how they can lead to the development of aneuploidy. One model system they used was colorectal tumors because they can be classified into two categories based on the type of genomic defects they contain. Diploid colorectal tumors have a normal number (1 - 2) of centrosomes (as determined by localization of centrosome proteins) while aneuploid colorectal tumors have localization of centrosome proteins to more than 2 discrete structures. They and others have postulated that these extra structures are directly responsible for the mis-segregation of chromosomes leading to aneuploidy and eventually tumor formation. This is seen very nicely in cells from mice lacking the p53, BRCA1 or ATM genes where aberrant partitioning of chromosomes is clearly visible.
The Effects of Genomic Alterations on Gene Expression
Following on the heels of earlier studies by Dr. Upender in the lab showing that introduction of an additional copy of a chromosome into cells results in an average increase in the expression levels of genes located on that chromosome, a similar analysis in tumors and tumor-derived cell lines was performed in collaboration with Drs. Ghadimi and Grade (Germany) and Dr. Camps (NIH). Because aneuploid tumors contain multiple chromosomes in a numerically unbalanced state, the effect is perhaps not surprisingly less pronounced. There remains in tumor cells, however, a high concordance between chromosome copy number and gene expression, particularly for those chromosomes that are characteristically affected in a particular tumor type. Their transcriptomic analysis of colorectal carcinomas and cell lines resulted in the identification of differentially expressed genes that have utlilty in predicting patient response to neo-adjuvant radiochemotherapy or as molecular targets for therapeutic intervention. More recent effort focused on the functional validation of these encoded proteins in the etiology of colorectal cancer and determine of whether perturbation of the biological pathways in which they are involved might have an adverse affect on the cancer phenotype. Such effects could be utilized in high-throughput screens to identify candidate compounds and eventually drugs for the treatment of colorectal cancer.
Ried T, Becker H, Difilippantonio M, Ghadimi M, Grade M, Liersch T, inventor; DHHS, assignee. Gene Expressing Profiling Predicts the Response of Rectal Carcinomas to Radiochemotherapy. Patent Pending, Filed in 2003. Application No. 10/585,725.