Alan Keith Meeker, Ph.D., M.A.T.

Headshot of Alan Keith Meeker
  • Co-director, Oncology Tissue and Imaging Services, Johns Hopkins Sidney Kimmel Comprehensive Care Center
  • Associate Professor of Pathology

Research Interests

Cancer; Quantitative fluorescence microscopy; Molecular pathology; Urology; Prostate cancer; Cancer biology; Telomeres; Pathology; Biology of aging; Cellular Senescence ...read more

Background

Dr. Alan Meeker is an Assistant Professor of Pathology, Oncology, Urology at the Johns Hopkins School of Medicine, as well as Biochemistry and Molecular Biology at the Johns Hopkins Bloomberg School of Public Health. Dr. Meeker co-directs the Histology, Immunohistochemistry, and slide scanning services in the Laboratory of Johns Hopkins Oncology Tissue and Imaging Services, and serves on the faculty of the Graduate Programs in Pathobiology, Cellular and Molecular Medicine, and Biochemistry and Molecular Biology. He joined the Hopkins faculty in 2006.

Dr. Meeker has spent his career studying cancer. His main research focus has been on chromosomal structures located at all chromosomal termini called, "telomeres." Telomeres have the unique property that they shorten each time a cell divides. This serves as the counting mechanism for a cell division clock, and if telomeres shorten significantly this will cause the cells possessing them to cease any further cell division; a process believed to be a protective mechanism for the prevention of cancer, a disease due in large part to uncontrolled cell division. However, in rare instances this protective barrier fails (e.g. due to random mutation), allowing cell populations to continue to divide, one consequence of which being very short telomeres. Such telomeres that are too short appear to contribute to the genetic instability, which is a major contributor to both cancer initiation and progression to more aggressive cancer behavior (e.g. metastatic spread). Telomeres are also believed to be related to human aging and the age-related phenomenon of cellular senescence; limiting cell division and thus impairing important activities, such as wound healing.

Dr. Meeker's primary studies on the relationship between shortened telomeres and cancer have mainly involved prostate, breast, pancreatic, and brain cancers. He was part of a Johns Hopkins team that developed a new quantitative fluorescence microscopy technique to measure telomere lengths directly in archival human tissues. In order for cancers to survive and advance, they must find a way to stop their telomeres from continuing to shorten so far that they become lethal to the cancer cells. Most cancers do this by abnormally activating a gene called telomerase that can counter-balance the telomere losses by synthesizing new telomere DNE on the ends of the chromosomes. Dr. Meeker's lab has also focused on the small but significant set of cancers that somehow maintain their telomeres without telomerase, so-called Alternative Lengthening of Telomeres cancers, or "ALT."  

The overall goal of these studies is to better understand telomere biology in cancer, thus providing new therapeutic targets to effectively treat this devastating disease.

In addition to the many academic papers he has published, Dr. Meeker also contributed chapters to the books Prostate Cancer: Biology, Genetics, and the New Therapeutics as well as Campbell-Walsh Urology, 10th and 11th ed

...read more

Titles

  • Co-director, Oncology Tissue and Imaging Services, Johns Hopkins Sidney Kimmel Comprehensive Care Center
  • Co-director, Cell Imaging Core, Johns Hopkins Sidney Kimmel Comprehensive Care Center
  • Co-Director of Immunohistochemistry
  • Associate Professor of Pathology
  • Associate Professor of Oncology
  • Associate Professor of Urology

Departments / Divisions

  • Oncology - Genitourinary Cancer Disease
  • Pathology - Kidney-Urologic Pathology
  • Urology

Centers & Institutes

Education

Degrees

  • B.S.; Florida Institute of Technology (Florida) (1983)
  • M.A.T.; Johns Hopkins University (Maryland) (1991)
  • Ph.D.; Johns Hopkins University School of Medicine (Maryland) (2001)

Additional Training

  • The Johns Hopkins University School of Medicine, Baltimore, MD, 2005, Postdoctoral research fellow

Research & Publications

Research Summary

Dr. Meeker has spent his career studying chromosomal structures called telomeres. Defective telomeres – specifically, those that are too short – appear to contribute to the genetic instability thought to cause the development and progression of many types of cancer.

Clearly seen at the chromosomal level in epithelial cancers such as prostate and breast cancers, the molecular mechanisms responsible for chromosome destabilization during carcinogenesis and progression have remained largely unknown.

To better understand these mechanisms, Dr. Meeker’s team worked with the DeMarzo Laboratory to develop a novel quantitative fluorescence microscopy technique to measure telomere lengths directly in archival tissues.

The team found that telomeres are indeed abnormally short in most microscopic precursor lesions in epithelial cancers – including those of the bladder, breast, cervix, colon, esophagus, gall bladder, oral cavity and prostate.

The belief is that those lesions are at risk of progressing to fully invasive carcinomas—and that telomere shortening may be useful in diagnosing cancer, as an intermediate endpoint marker in chemoprevention studies, and as a valid prevention target in its own right.

The telomere-length assay, which features single-cell resolution, can be used to test the hypothesized link between telomere shortening and human aging.

Lab

The primary focus of my research activities for the last 2 decades has been on cancer-associated abnormalities in telomere biology. My research discoveries provide significant supporting data that telomere biology plays multiple important roles in the disease process. For example, using a novel tissue-based assay I developed while a postdoc in the laboratory of Dr. Angelo De Marzo, we found that the majority of pre-malignant lesions display severe telomere shortening; thus, this genomic abnormality arises very early in the disease process, likely contributing significantly to the process of malignant transformation by instigating chromosomal instability. Other key discoveries in the lab include the finding of widespread telomere shortening in the breast epithelium of normal women, the finding that tissue-based telomere length measurements are significantly associated with cancer risk and clinical outcomes among prostate cancer patients, and the discovery of a strong association between recurrent, inactivating mutations in the ATRX or DAXX genes and cancers utilizing a telomerase-independent telomere maintenance mechanism termed ALT. In addition to my primary focus on telomere biology I also perform studies on in situ tumor biomarker development and in vitro drug screening for anti-cancer agents, and maintain an interest in the biology of aging and cellular senescence, particularly how this may relate to cancer risk and progression.

Lab Website: Meeker-Heaphy Lab

Clinical Trials

Learn more about clinical trials at the Johns Hopkins Kimmel Cancer Center.

Selected Publications

Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus GJ, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Marie SK, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK. Altered Telomeres in Tumors with ATRX and DAXX Mutations. Science. 2011;22:333; 425. PMID: 21719641 PMCID: PMC3174141

Heaphy CM, Yun GS, Peskoe SB, Joshu CE, Lee TK, Giovannucci E, Mucci LA, Kenfield SA, Stampfer MJ, Hicks JL, De Marzo AM, Platz EA, Meeker AK. Prostate Cancer Cell Telomere Length Variation and Stromal Cell Telomere Length as Prognostic Markers for Metastasis and Death. Cancer Discovery. 2013;Oct; 2(10):1130-41. PMID:23779129

Brosnan-Cashman JA, Yuan M, Graham MK, Rizzo AJ, Myers KM, Davis C, Zhang R, Esopi DM, Raabe EH, Eberhart CG, Heaphy CM, Meeker AK. ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner. PLoS One. 2018 Sep 18;13(9) PMID: 30226859

Graham MK, Kim J, Da J, Brosnan-Cashman JA, Rizzo A, Baena Del Valle JA, Chia L, Rubenstein M, Davis C, Zheng Q, Cope L, Considine M, Haffner MC, De Marzo AM, Meeker AK, Heaphy CM. Functional Loss of ATRX and TERC Activates Alternative Lengthening of Telomeres (ALT) in LAPC4 Prostate Cancer Cells. Molecular Cancer Research. 2019 Dec;17(12):2480-2491. PMID: 31611308

Esopi D, Graham MK, Brosnan-Cashman JA, Meyers J, Vaghasia A, Gupta A, Kumar B, Haffner MC, Heaphy CM, De Marzo AM, Meeker AK, Nelson WG, Wheelan SJ, Yegnasubramanian S. Pervasive promoter hypermethylation of silenced TERT alleles in human cancers. Cell Oncology. 2020 May 28. PMID: 32468444

Patents

Somatic Mutations In Atrx In Brain Cancer
Patent # 14/129,850 | 

Was filed as PCT International Application Number PCT/US2012/044631, filed on June 28, 2012, and as U.S. Provisional Application No. 60/502,646, filed on June 29, 2011 and as U.S. Application Serial Number 14/129,850, filed on December 27, 2013

Contact for Research Inquiries

Department of Pathology
411 N. Caroline Street

Email me

Academic Affiliations & Courses

Graduate Program Affiliation

Pathobiology Graduate Program, Department of Pathology

Cellular and Molecular Medicine, Johns Hopkins School of Medicine

Biochemistry and Molecular Biology Graduate Program, Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health

Courses and Syllabi

  • Stem Cells and the Biology of Aging and Disease (PH.120.627)
  • Cancer Biology (PH.120.624)
  • Phenotyping for Functional Genetics (ME:680.712)
  • Biological Basis of Aging (260.665.01)
  • Stem Cells and the Biology of Aging and Disease (AS.020.337)
  • Introduction To The Human Body: Anatomy, Histology and Physiology (ME: 800.702)

Activities & Honors

Honors

  • The Paul Ehrlich Research Award, Johns Hopkins School of Medicine, Baltimore, MD.
  • AACR-AFLAC Scholar-in-Training Awards, American Association for Cancer Research and AFLAC
  • Best Scientific Session for "“Improved Software for Quantitative Analysis of Fluorescence Microscopy Images.”, Advancing Practice Instruction and Innovation through Informatics (APIII)
  • ASIP Merit Award, American Society for Investigative Pathology
  • Young Investigator Award, David Koch/Prostate Cancer Foundation
  • AACR Team Science Award, American Association for Cancer Research (AACR)

Memberships

  • American Association for Cancer Research

    Active member.

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Videos & Media

Lectures and Presentations

  • Telomere Dynamics, Genetic Instability and Cancer
    Podium talk, Baltimore Area Repair Symposium, Baltimore, MD (03/10/2012)
    Baltimore Area Repair
  • Exomic Sequencing in Pancreatic NETs: Potential Clinical Applications
    Podium talk, VIII Simposio Internacional GETNE, Seville, Spain (05/14/2012)
    GETNE (Grupo Espanol de Tumores Neuroendocrinos)
  • Epigenetics of Pancreatic Neuroendocrine Tumors.
    Podium talk, European Neuroendocrine Tumor Society 2013 Annual Conference, Barcelona, Spain (04/21/2013)
    European Neuroendocrine Tumor Society (ENETS)
  • Telomere Translation: Moving Telomere Research From Bench to Bedside to Benefit Cancer
    Podium talk, International Conference on Genomic Medicine, Baltimore, MD. (02/10/2017)
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