Nature：研究发现一种改进的癌症模型

生物谷

作者简介：

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

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 Einstein College of Medicine Distinguished Alumnus Award, 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

Tonon G, Wong KK, Maulik G, Brennan C, Feng B, Zhang Y, Khatry DB,Protopopov A, You MJ, Aguirre AJ, Martin ES, Yang Z, Ji H, Chin L, Depinho RA. High-resolution genomic profiles of human lung cancer. Proc Natl Acad Sci U S A 2005;102:9625-30.

Aguirre AJ, Brennan C, Bailey G, Sinha R, Feng B, Leo C, Zhang Y, Zhang J, Gans JD, Cauwels C, Cordon-Carlo C, Redston MS, DePinho RA, Chin L. High-resolution characterization of the pancreatic adenocarcinoma genome. Proc Natl Acad Sci 2004;101:9067-72.

Bachoo RM, Kim RS, Ligon KL, Maher EA, Brennan C, Billings N, Chan S, Li Ca, Rowitch DH, Wong WH, DePinho RA. Molecular diversity of astrocytes with implications for neurological disorders. Proc Natl Acad Sci U S A 2004;101:8384-9.

Sharpless NE, Ramsey MR, Balasubramanian P, Castrillon DH, DePinho RA. The differential impact of p16(INK4a) or p19(ARF) deficiency on cell growth and tumorigenesis. Oncogene 2004;23:379-85.

Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J, Redston MS, DePinho RA. Activated Kras G12D and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma in the mouse. Genes Dev 2003;17:3112-26.

Castrillon DH, Miao L, Kollipara R, Horner JW, DePinho RA. Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science 2003;301:215-8.

Chang S, Khoo CM, Naylor ML, Maser RS, DePinho RA.
Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. Genes Dev 2003;17:88-100.

Farazi PA, Glickman J, Jiang S, Yu A, Rudolph KL, DePinho RA. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res 2003;63:5021-7.

Wong KK, Maser RS, Bachoo RM, Menon J, Carrasco DR, Gu Y, Alt FW, DePinho RA. Telomere dysfunction and ATM deficiency deplete stem cell reserves and accelerate aging. Nature 2003;4421:643-8.

Instructors

Robert Bachoo, MD, PhD

Elizabeth Maher, MD, PhD

Giovanni Tonon, MD, PhD

Associates

Gerry Chu, MD, PhD

Jan-Hermen Dannenberg, PhD

Aram Hezel, MD

Mariela Jaskelioff, PhD

Alec Kimmelman, MD, PhD

Eric Martin, PhD

Richard Maser, PhD

Ji-Hye Paik, PhD

Erguen Sahin, MD

Alexander Stegh, PhD

Jayne Stommel, PhD

Hongwu Zheng, PhD

相关基因：

FBXW7

Official Symbol FBXW7 and Name: F-box and WD repeat domain containing 7 [Homo sapiens]
Other Aliases: AGO, CDC4, DKFZp686F23254, FBW7, FBX30, FBXW6, SEL-10, SEL10
Other Designations: F-box and WD-40 domain protein 7 (archipelago homolog, Drosophila); F-box protein FBW7; F-box protein SEL-10; archipelago homolog; archipelago, Drosophila, homolog of; homolog of C elegans sel-10
Chromosome: 4; Location: 4q31.3
Annotation: Chromosome 4, NC_000004.10 (153675621..153461859, complement)
MIM: 606278
GeneID: 55294

PTEN

Official Symbol PTEN and Name: phosphatase and tensin homolog (mutated in multiple advanced cancers 1) [Homo sapiens]
Other Aliases: BZS, MGC11227, MHAM, MMAC1, PTEN1, TEP1
Other Designations: MMAC1 phosphatase and tensin homolog deleted on chromosome 10; mutated in multiple advanced cancers 1; phosphatase and tensin homolog
Chromosome: 10; Location: 10q23.3
Annotation: Chromosome 10, NC_000010.9 (89613174..89716381)
MIM: 601728
GeneID: 5728