Norman E. Sharpless, MD

Norman E. Sharpless, MD

Professor of Medicine & Genetics
Chair, The Lineberger Comprehensive Cancer Center

Research Interests

Key words: cancer genetics, tumor suppressor genes, mouse tumor models, cell cycle and senescence

The lab relies on murine genetic approaches to study the roles of the INK4/ARF tumor suppressor locus in human cancer and aging. At present, the lab has two main focuses:

Stem Cell Aging:

Cancer and degenerative diseases are much more common in old people than young.  Although this has been well-recognized in clinical medicine for decades, scientists do not agree as to why this occurs.  Recently, work from several labs including our own has shown that humans age, in part, because important regenerative cells lose their capacity to divide with the passage of time.  That is, the tissues and organs from old people are less able to replace and regenerate lost or damaged cells than the corresponding tissues and organs from young people.  Our lab has studied mechanisms that underlie this age-dependent failure of cell division; in fact, we have shown the surprising result that cellular programs that function to prevent cancer untowardly also calls aging.   Specifically, cellular “senescence” is now believed to be of major importance in the process of aging.  Senescence refers to a permanent growth arrest induced in formerly dividing cells by the activation of genes that prevent cancer.  The good news in this system is that the normal functioning of these ‘tumor suppressor genes’ prevents cancer; the bad news is that these same genetic events appear to cause aging by activating cellular senescence.

Our principal contributions in this area have been to elucidate the relationship between senescence and aging:

  1. We have shown that the expression of p16INK4a, an important promoter of senescence, increases markedly with aging.  Therefore, expression of p16INK4a can serve as a ‘biomarker’ of physiologic, as opposed to chronologic, age.  Such a molecular biomarker should help in several clinical settings: for example to forecast the onset of future disease and to predict the efficacy of ‘anti-aging’ compounds.
  2. We have shown that the activation of senescence mechanisms occurs in certain self-renewing and stem cell compartments with aging.  Therefore, we grow old in part because our adult stem cells grow old.  Additionally, we can retard aging in some of these stem cells by impairing senescence.
  3. We have shown that the failure of senescence in these same stem cell compartments leads to cancer.  Therefore, cancer and aging respectively represent the failure or success of senescence in discrete stem cell compartments.
  4. We have identified a specific biochemical property of tissue-specific stem cells that allows us to protect them from the pro-aging effects of DNA damage.  This observation is important because it makes it possible to spare normal stem cells from the toxicity of chemotherapy and radiation without sparing abnormal stem cells that exist within a cancer.  Therefore, cancer therapy will be made more effective and less toxic by this observation.

A surprising finding related to this work has been the discovery that humans with different ‘set points’ to activate cellular senescence differ in their predisposition to cancer and certain age-related diseases such as type II diabetes and atherosclerotic disease.

Melanoma and Murine Models of Cancer:

Because of the important role of p16INK4a in preventing melanoma, the lab has long been interested in this particularly deadly form of skin cancer. Specifically, we are interested in using genetically engineered models of cancer to study melanoma genetics. We have shown a role for the p16INK4a-RB and ARF-p53 tumor suppressor pathways in repressing this important human cancer in response to RAS-RAF activation. We have generated highly faithful models of human melanoma, and have used these to study novel therapeutics. We have also discovered a novel human melanoma sub-type based on expression profiling, and have identified a new therapeutic target (CD200) for treatment of melanoma.

Moreover, with the Perou Lab at UNC, we have developed the UNC Mouse Phase I Unit (the MP1U). The UNC MP1U was established in 2006 to facilitate the pre-clinical development of novel anti-cancer therapeutics in highly faithful genetically engineered murine models of human cancer. The MP1U has extensive capabilities for serial radiographic imaging; pharmacology and pharmacokinetics; and molecular target validation. In particular, the MP1U is particularly valuable for optimizing a treatment regimen and schedules, a very difficult task in human systems. We have several ongoing studies using novel candidate therapies developed in academia or industry, and these translational efforts are having an ongoing influence on the clinical development of human anti-cancer therapies.


PubMed graphic

Selected Publications:

Representative Original Publications:

Sharpless NE, Bardeesy N, Lee KH, Carrasco R, Castrillon DH, Aguirre A, Wu E, Horner JW, DePinho RA Loss of p16INK4a with Retention of p19ARF Predisposes to Tumourigenesis in Mice. Nature 2001; 413(6851):86-91.

Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, and Sharpless NE. Ink4a/Arf expression is a biomarker of aging. J Clin Invest, 2004; 114: 1299-307.

Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, and Sharpless NE. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature, 2006; 443, 453-457.

Shields JM, Thomas NE, Cregger M, Berger AJ, Leslie M, Torrice C, Hao H, Penland S, Arbiser J, Scott G, Zhou T, Bar-Eli M, Bear JE, Der CJ, Kaufmann WK, Rimm DL, Sharpless NE. Lack of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Shows a New Type of Melanoma. Cancer Res, 2007 Feb 15;67(4):1502-1512.

Ramsey MR, Krishnamurthy J, Pei XH, Torrice C, Lin W, Carrasco DR, Ligon KL, Xiong Y, Sharpless NE. Expression of p16INK4a Compensates for p18INK4c Loss in Cyclin-Dependent Kinase 4/6-Dependent Tumors and Tissues. Cancer Res, 2007 May 15;67:4732-4741.

Ji H, Ramsey MR. Hayes DN, Fan C, McNamara K, Kozlowski P, Torrice C, Wu MC, Shimamura T, Perera S, Liang MC, Cai D, Naumov GN, Bao L, Contreras C, Li D, Chen L, Krishnamurthy J, Koivunen J, Chirieac LR, Padera R, Bronson RT, Lindeman NI, Christiani DC, Lin X, Shapiro GI, Jänne PA, Johnson B, Meyerson M, Kwiatkowski DJ, Castrillon DH, *Bardeesy N, *Sharpless NE, *Wong KK. LKB1 modulates lung cancer differentiation and metastasis. Nature, 2007 Aug 16;448(7155):807-810. (*=corresponding authors).

Petermann KB, Rozenberg GI, Zedek D, Groben P, McKinnon K, Buehler C, Kim WY, Shields JM, Penland S, Bear JE, Thomas NE, Serody J, Sharpless NE. CD200 is induced by ERK and is a potential therapeutic target in melanoma. J Clin Invest, 2007 Dec;117(12):3922-3929.

Liu Y,Sanoff HK, Cho H, Burd CE, Torrice T, Mohlke KL, Ibrahim JG, Thomas NE, Sharpless NE. INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis. PLoS One, 2009;4(4):e5027.

Liu Y,Sanoff HK, Cho H, Burd CE, Torrice T, Ibrahim JG, Thomas NE, Sharpless NE. Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell, 2009 Aug;8(4):439-48.

Tsygankov D, Liu Y, Sanoff HK, Sharpless NE*, Elston TC*. A quantitative model for age-dependent expression of the p16INK4a tumor suppressor. Proc Natl Acad Sci USA, 2009 Sep 29;106(39):1652-7. (*=corresponding authors).

Representative Scientific Reviews:

Bell, JF, Sharpless NE. Telomeres, p21 and the cancer-aging hypothesis. Nat Genet, 2007. 39(1): 11-2.

Kim, W. and Sharpless, NE.  The Regulation of INK4/ARF in Cancer and Aging.  Cell.  2006 Oct 20;127(2):265-75.

Sharpless NE, and Depinho RA. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov 2006; 5, 741-754.

Lay Press:

British Broadcasting Service. Hope for test to measure ageing, June 16th, 2009.

Discover Magazine, Ruvinsky, J. Raw Data: Is Cancer the Price of Longevity? The same protein that prevents cancer may also encourage aging. Septmeber 12th, 2006.

National Public Radio, Palca, J. Research on Cancer Gene Poses a Dilemma, , September 6th, 2006.

The New York Times, Wade, N. Gene Called link Between Life Span and Cancers. September 7th, 2006.

WebMD, Hitti, M. How Old Are You Inside? Blood Test May Tell, June 18th, 2009.


Current Lab Members

  • Andrew Lin, Undergraduate researcher
  • S. Johnson, MD-PhD candidate
  • W. Jeck , MD-PhD candidate
  • S. Hanna, PhD candidate (Co-Mentoree with W. Kim)
  • J. Sorrentino, PhD candidate
  • P. Dillon, MD, Postdoctoral Fellow
  • Y. Liu, PhD, Postdoctoral Fellow
  • P. Roberts, PhD PharmD, Postdoctoral Fellow
  • G. Rozenberg, PhD, Postdoctoral Fellow
  • W. Liu, PhD, Postdoctoral Fellow
  • A. Seibold, PhD, Postdoctoral Fellow
  • K. Janakiraman, Research Associate
  • J. Strum, Research Associate
  • J. Bisi, Research Associate
  • K. Fu, Research Technician
  • K. Bendt, Research Technician
  • C. Torrice, Research Technician

Former Trainees

Current Position

  • S. Apisarnatharax, MD
Assistant Professor of Radiation Oncology, The University of Pennsylvania, Philadelphia, PA
  • J. Bell, MD
Assistant Professor, Carolinas Medical Center, Charlotte, NC
  • William Kim, MD
Assistant Professor of Medicine, UNC-CH, Chapel Hill, NC
  • K. Monahan, PhD
Post-doctoral Fellow, UNC-CH, Chapel Hill, NC
  • S. Pendland, MD
Private Practice, Great Falls Clinic, Great Falls, Montana
  • M. Ramsey, PhD
Post-doctoral Fellow, Massachusetts Gen. Hospital, Harvard Medical School
  • H. Sanoff, MD
Assistant Professor of Medicine, The University of Virginia, Charlottesville, VA