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.
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
Learn more about clinical trials at the Johns Hopkins Kimmel Cancer Center.
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, Subhawong AP, Hong SM, Goggins MG, Montgomery EA, Gabrielson E, Netto GJ, Epstein JI, Lotan TL, Westra WH, Shih IeM, Iacobuzio-Donahue CA, Maitra A, Li QK, Eberhart CG, Taube JM, Rakheja D, Kurman RJ, Wu TC, Roden RB, Argani P, De Marzo AM, Terracciano L, Torbenson M, Meeker AK. Prevalence of the Alternative Lengthening of Telomeres (ALT) Telomere Maintenance Mechanism in Human Cancer Subtypes. Am Jol Pathology. 2011;179(4):1608-1615. PMID: 21888887
Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, de Lange T, De S, Petrini JH, Sung PA, Jasin M, Rosenbluh J, Zwang Y, Weir BA, Hatton C, Ivanova E, Macconaill L, Hanna M, Hahn WC, Lue NF, Reddel RR, Jiao Y, Kinzler K, Vogelstein B, Papadopoulos N, Meeker AK. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet. 2012; 8(7):e1002772. Epub 2012 Jul 19
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
Graham, M, Meeker, A.K. The role of telomeres and telomerase in prostate cancer development and therapy. Nature Reviews Urology. 2017 Jul 4. [Epub ahead of print]