Researcher Profile
Ronald A. DePinho, MD
Professor of Medicine, Harvard Medical School
Department
Medical Oncology/Molecular and Cellular
Area of Research
Cancer-Senescence Pathways in Normal and Neoplastic Processes
Contact Information
Ronald A. DePinho, MDDana-Farber Cancer Institute
44 Binney Street
Mayer 413
Boston, MA 02115
Office phone: (617) 632-6086
Fax: (617) 632-6069
E-mail: ron_depinho@dfci.harvard.edu
Web site: The DePinho Lab
Preferred contact method: office phone
Research
Our research program is devoted to the analysis of pathways governing the genesis, progression, and maintenance of cancer. Utilizing the mouse as a model system, we have sought to understand the role and regulation of cellular-senescence pathways, telomere-based crisis, and host-tumor interactions on the molecular, cellular, and organismal levels.
The Myc superfamily
The actions of the Myc oncoprotein are opposed by members of the Mad (Mxi1) family of transcriptional repressors. We and others have demonstrated that Mad/Mxi1 functions as a bona fide tumor suppressor pathway. Current efforts are focused on characterizing the Sin3 corepressor complex and understanding how its components participate in the processes of development, cancer, and aging.
RB/p53/INK4a
Inactivation of the p16-RB and AFF-p53 pathways appear to be obligate events in the transformation of mouse and human cells. We have established that Ink4a/Arf functions as a potent tumor suppressor in the mouse, and its loss of function promotes the development of a broad spectrum of cancers including malignant melanoma and glioblastoma. Our more recent studies of the p16(Ink4a)-specific knockout have pointed to p16(Ink4a) as a key factor in the prevention of cancers linked to environmental carcinogens.
Telomere biology
Telomerase activity is upregulated in the vast majority of human cancers and may play a role in facilitating cancer progression. In collaboration with Carol Grieder, we generated a mouse null for the essential RNA component of telomerase and studied the impact of telomerase deficiency and telomere dysfunction on the initiation and progression of cancer. We observed that loss of telomere dysfunction provokes high levels of genomic instability, particularly amplifications and deletions, and these aberrations allow would-be cancer cells to achieve the threshold of changes needed to initiate the cancer process.
Mouse models of human cancer
We continue to construct refined mouse models of human cancer. Our goals are to (1) connect genotype and phenotype, i.e., explain how certain genetic lesions influence specific tumor biological processes; (2) determine which genetic lesions play essential roles in tumor maintenance; and (3) utilize these models to discover new cancer genes and biomarkers useful in the assessment of anticancer compounds in clinical trials. The principal models under development include malignant melanoma, glioblastoma, pancreatic cancer, and colorectal cancer.
Recent Awards
- Albert Szent-Gyrgyi Prize for Progress in Cancer Research, 2009
- Helsinki Medal, 2007
- Albert Einstein College of Medicine Distinguished Alumnus Award, 2004
- American Cancer Society Edith A. Pistorino Research Professorship, 2004
- Member, Institute of Medicine of the National Academies, 2004
- AACR-G.H.A. Clowes Memorial Award, 2003
- American Society for Clinical Investigation Award, 2002
- American Society for Clinical Investigation Award, 2000
Biography
Dr. DePinho received his MD with distinction from Albert Einstein Medical College in 1981. He later completed his research training at Columbia Presbyterian Hospital, and in 1998, joined DFCI, where his laboratory has dissected the roles of Myc, Rb, p53, and telomerase in cancer and senescence.
Select Publications
- Wong KK, Maser RS, Bachoo RM, Menon J, Carrasco DR, Gu Y, Alt FW, DePinho RA. (2003). Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421,643-8.
- Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL, Brennan C and others. (2007). Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318,287-90.
- Maser RS, Choudhury B, Campbell PJ, Feng B, Wong KK, Protopopov A, O'Neil J, Gutierrez A, Ivanova E, Perna I and others. (2007). Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 447,966-71.
- Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR and others. (2007). FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128,309-23.
- Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, Perry SR, Tonon G, Chu GC, Ding Z and others. (2008). p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 455,1129-33.
- Paik, JH, Ding, Z, Narurkar, R, Ramkissoon, S, Muller, F, Kamoun, WS, Chae, SS, Zheng, H, Ying, H, Mahoney, J, Hiller, D, Jiang, S, Protopopov, A, Wong, WH, Chin, L, Ligon, KL and DePinho, RA. (2009). FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540-553.
- Reviews covering the major areas of research in our laboratory (see below):
- Hezel, AF, Kimmelman, AC, Stanger, BZ, Bardeesy, N and Depinho, RA. (2006). Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 20, 1218-1249.
- Furnari, FB, Fenton, T, Bachoo, RM, Mukasa, A, Stommel, JM, Stegh, A, Hahn, WC, Ligon, KL, Louis, DN, Brennan, C, Chin, L, DePinho, RA and Cavenee, WK. (2007). Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21, 2683-2710.
- Artandi, SE and Depinho, RA. (2009). Telomeres and telomerase in cancer. Carcinogenesis.
