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

Web Page: The DePinho Lab Page
16 postdoctoral fellows, 2 graduate students

The DePinho laboratory studies the molecular and biological processes governing the development of cancer, the basis for aging and degenerative diseases, and the maintenance of normal and cancer stem cells. The laboratory takes an integrated genomics and biological systems approach to (i) discover and validate oncogenes and tumor suppressor genes, (ii) elucidate the mechanisms driving cancer-associated chromosomal instability with an emphasis on telomeres and DNA damage checkpoint pathways, (iii) define the role of stem cells and cancer stem cells and related developmental pathways in origins and maintenance of tumors, (iv) the development and characterization of mouse models of human cancer particularly pancreas, colon, brain, breast and lymphoid systems, and (v) the discovery and development of novel cancer therapies directed against newly discovered and rigorously validated oncogenes.

Some of our ongoing efforts have centered on how mouse genetics and genomics can be used to dissect the molecular mechanisms and biological processes governing the genesis and maintenance of tumorigenesis. We have previously worked on the Myc superfamily of oncoproteins (Myc) and tumor suppressors (Mad) and defined 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. We discovered 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. Other tumor suppressor pathway studies have elucidated the genetic and biochemical relationship between Rb, p53 and PI3K pathways, particularly p16INK4a, p19ARF and FoxOs, and have delineated an intimate link between pathways that control cellular senescence and those that regulate cell cycle entry or cell survival as well as stem cell homeostasis.

In our multi-disciplinary programs in glioblastoma (GBM) and Pancreas Cancer (PDAC), two of the most lethal human cancers, we are addressing a number of questions central to pathogenesis including (i) the tumor's cell of origin and how the state of cellular differentiation influences the oncogenic actions of prominent glioma-relevant mutations, (ii) how such mutations contribute to specific biological and clinical characteristics of the disease, and (iii) whether these are required for both the genesis and maintenance of these cancers and whether such knowledge can inform drug development.

A major program in the lab has studied 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:

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 tumours 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.
Zheng H., Ying H., Yan H., Kimmelman AC., Hiller DJ., Chen AJ., Perry SR., Tonon G., Chu GC., Ding Z., Stommel JM., Dunn KL., Wiedemeyer R., You MJ., Brennan C., Wang YA., Ligon KL., Wong WH., Chin L., and DePinho RA (P53 and Pten Control Neural and Glioma Stem/Progenitor Cell Renewal and Differentiation. Nature. 2008 Oct 23;455:1129-33.

BBS webpage updated 12/02/2009