Ronald A. DePinho

Department of Medicine and Genetics
Harvard Medical School, Dana-Farber Cancer Institute
Mayer Building, Room 413
44 Binney Street
Boston, MA 02115
Tel:(617) 632-6085
Fax: (617) 632-6069
Email: ron_depinho@dfci.harvard.edu
15 postdoctoral fellows, 2 graduate students

The DePinho laboratory has exploited mouse genetics and genomics to dissect the molecular mechanisms and biological processes governing the genesis and maintenance of tumorigenesis.  Analysis of the Myc Superfamily of oncoproteins (Myc) and tumor suppressors (Mad) have focused on the physical and functional interactions among its members and how these interactions regulate gene expression at the level of chromatin and thereby control the growth and development of normal and neoplastic cells.  The observation that Mad acts to repress transcription and suppress cancer in vivo, along with our discovery of the mSin3 chromatin remodeling complex, has defined a mechanistically distinct tumor suppressor pathway.  We have also explored the genetic and biochemical relationship between Rb and p53 pathways, particularly p16INK4a and p19ARF, have delineated an intimate link between pathways that control cellular senescence and those that regulate cell cycle entry or cell survival.

We have developed a program in glioblastoma (GBM), the most common and deadliest of adult human brain tumors.  Specifically, questions central to glioma pathogenesis are being addressed including:  1) the tumor's cell of origin and how the state of cellular differentiation influences the oncogenic actions of prominent glioma-relevant mutations, 2) how such mutations contribute to specific biological and clinical characteristics of the disease, and 3) whether these are required for both the genesis and maintenance of gliomas.

We have also developed a program to understand the role of telomerase in cancer, development and aging, and how telomere dynamics inter-relate to DNA damage and recombination pathways.  Finally, our construction of inducible cancer models has permitted an in vivo analysis of the complex symbiotic host-tumor cell interactions central to tumor maintenance and progression of diverse types of cancers.

References:

• Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, Hezel AF, Horner J, Lauwers GY, Hanahan D, Depinho RA.   Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006 Nov 15;20(22):3130-46.
• Paik J-H, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothava Z, Horner JW, Carrasco DR, Jiang S. Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA.  FoxO factors are lineage-restricted redundant tumor suppressors and critical regulators of endothelial cell homeostasis.  Cell. 2007 Jan 26;128(2):309-23.
• Maser RS, Choudhury B, Campbell PJ, Feng B, Wong KK, Protopopov A, O’Neil J, Gutierrez A, Ivanova E, Perna I, Lin E, Mani V, Jiang S, McNamara K, Zaghlul S, Edkins S, Stevens C, Brennan C, Martin ES, Wiedemeyer R, Kabbarah O, Nogueira C, Histen G, Aster J, Mansour M, Duke V, Foroni L, Fielding AK, Goldstone AH, Rowe JM, Wang YA, Look AT, Stratton MR, Chin L, Futreal PA, Depinho RA.  Chromosomally unstable mouse tumors have genomic alterations similar to diverse human cancers. Nature. 2007; 447:966-71.
• Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL, Brennan C, Chin L, DePinho RA.  Co-activation of receptor tyrosine kinases affects response to targeted therapies.  Science 2007;318:287-290.