WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

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Cancer arises by a multi-step process involving activation of oncogenes and inactivation of tumor suppressor genes. To become fully invasive and metastatic, tumors must acquire capabilities that non-neoplastic differentiated somatic cells do not normally possess. The acquisition of these changes is propelled by destabilization of the genome, which arises in different forms. Subtle changes such as point mutations in single nucleotides occur as do whole chromosome gains and losses, referred to as aneuploidy. Almost all cancers are aneuploid, yet insight into how they become aneuploid and the effects that aneuploidy has on tumor formation have been unclear until recently.

We have focused on understanding how mitotic regulators that function during metaphase alter chromosome segregation when defective. Our initial studies have identified MAD2 and securin as two genes whose regulation during mitosis is critical for proper chromosome segregation. MAD2 is an inhibitor of the Anaphase Promoting Complex, an E3 ligase that ubiquitinates securin at metaphase. Securin is a multi-functional molecule that keeps the chromosomes bound together until they are correctly aligned on the mitotic spindle. We have found that partial loss of function of MAD2 interferes with the timing of securin degradation resulting in chromosome missegregation and aneuploidy. Our work has also revealed that MAD2+/- mice are tumor prone, defining MAD2 as a haploinsufficient tumor suppressor. Consistent with this, several malignancies such as breast and ovarian cancer exhibit low MAD2 levels in a subset of tumors. Paradoxically, MAD2, which is an E2F target gene, is also overexpressed in some tumors and increased levels of MAD2 results in delayed securin degradation and chromosome missegregation.

Further investigations in this laboratory are committed to answering two questions:

What are the mechanisms that promote genomic instability in cancer?

Can we identify specific molecular targets of genome destabilizing events that are essential for the tumor phenotype and validate these as therapeutic targets in preclinical models of cancer?

To these ends, we have knocked out specific genes by homologous recombination in non-cancerous human cells resulting in the induction of genomic instability and transformation. Using these cells as a model of the transition to neoplasia, in conjunction with microarray analysis, we have identified several genes that appear to be essential for the neoplastic transformation and maintenance of the tumor phenotype. The role of these genes in tumorigenesis is currently being studied in vitro by RNA interference technology. Longer term projects will include making targeted deletions in mice of specific proteins identified in these screens, and using antibody, peptide, and RNA technology, validating these genes as possible drug targets in preclinical models.

Abnormal spindle formation in the absence of MAD2 as seen by indirect immunofluorescence microscopy Shown are various degrees of abnormal or incomplete spindle formation in MAD2 knockdown HaCaT cells (A–C) and HeLa cells (D–F). (G and H) Normal spindle formation in prometaphase and metaphase lamin HeLa knockdown cells. DNA is marked by DAPI in blue and beta-tubulin is in green. From: Michel L, Diaz-Rodriguez E, Narayan G, Hernando E, Murty VV, Benezra R Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. Proc Natl Acad Sci U S A 2004 Mar 30;101(13):4459-64

Education

1983	BA (chemistry), Emory University, Atlanta, GA
1988	MD, Case Western Reserve University School of Medicine, Cleveland, OH
1993	MBA (finance), Columbia Graduate School of Business, New York, NY

Post-graduate Training

1988-1989	Internship in Medicine, Cleveland Clinic Foundation, Cleveland, OH
1992-1994	Research Fellow, laboratory of Arthur Bank, Division of Hematology and Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, NY
1994-1996	Resident in Medicine, Mount Sinai Medical Center, New York, NY
1996-1999	Fellowship in Hematology/Oncology, Memorial Sloan-Kettering Cancer Center and the New York Hospital, Cornell University Medical College, New York, NY
1999-2004	Research Fellow, laboratory of Robert Benezra, Cell Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY
1999-2004	Fellow in Medicine, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY

Academic Positions & Employment

1989-1992	The Genesis Group, Pharmaceutical and Biotechnology Industry Consultants, Montclair, NJ
2004-present	Assistant Professor, Department of Medicine, Washington University, St. Louis, MO

Board Certification

1996	Diplomate, American Board of Internal Medicine
1999	Diplomate, American Board of Medical Oncology

Honors & Awards

1998-2000	Clinical Scholars Award, Memorial Sloan-Kettering Cancer Center
2001-2002	Fellowship in Basic Research, AACR-Sidney Kimmel Foundation for Cancer Research
2001-2006	Mentored Clinical Scientist Development Award (K08), NIH

Memberships

	American Society of Clinical Oncology
	American Association for Cancer Research

Updated: February 1, 2005