Associate Professor
Pathology Department, School of Medicine
RESEARCH OVERVIEW
The primary focus of the Meeker lab over the last 2 decades has been on cancer-associated abnormalities in telomere biology. Telomeres are repetitive DNA elements located at chromosomal termini that serve to maintain chromosomal stability and act as a buffer against progressive DNA losses that occur during cell division. Our earlier discoveries highlighted the roles that telomere abnormalities play in human cancer, including initiation and disease progression. Using a novel telomere-specific FISH assay, we found that the vast majority of pre-malignant carcinoma lesions harbor severe telomere shortening; thus, this abnormality arises very early during the process of tumorigenesis - likely contributing significantly to malignant transformation via chromosomal instability due to telomere dysfunction. We discovered significant, widespread telomere shortening in normal-appearing breast ductal epithelial cells in normal adult women, and this may be linked to hormone-dependent, cyclical waves of proliferation and involution in this particular cell population; perhaps helping to explain why these particular cells are at such high risk for malignant transformation. Currently we are testing whether telomere length measurements may help predict breast cancer risk. In other translational work, we found that telomere length is a strong prognostic predictor of cancer aggressiveness in prostate cancer.
Another focus of the lab is on telomere maintenance in cancer. Most cancer cells prevent total loss of telomeres by inappropriate expression of the telomere-synthesizing enzyme, telomerase. However, a significant minority of cancers instead use a poorly understood genetic recombination mechanism known as alternative lengthening of telomeres (ALT). In conjunction with colleagues here at the Johns Hopkins Comprehensive Cancer Center, our lab discovered the first ALT-suppressor genes in human cancer, ATRX and DAXX, two chromatin-remodeling factors that harbor inactivating mutations in ALT-positive cancers. Currently, we are working to understand how these ALT-suppressors function at the molecular level.
In non-malignant cells, telomere loss causes permanent cell cycle exit (“replicative senescence”), and, if not eliminated, such cells may promote cancer initiation and progression in the local tissue environment. We are currently assessing whether the prevalence and/or phenotype of senescent prostate cells in the stromal compartment is linked to prostate cancer initiation and/or progression. If so, this could lead to clinical tests for gauging prostate cancer risk and predicting disease behavior in prostate cancer patients.
Selected Publications
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.
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.
Diplas BH, He X, Brosnan-Cashman JA, Liu H, Chen LH, Wang Z, Moure CJ, Killela PJ, Loriaux DB, Lipp ES, Greer PK, Yang R, Rizzo AJ, Rodriguez FJ, Friedman AH, Friedman HS, Wang S, He Y, McLendon RE, Bigner DD, Jiao Y, Waitkus MS, Meeker AK, Yan H. The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma. Nature Communications, 2018.
Bell WR, Meeker AK, Rizzo A, Rajpara S, Rosenthal IM, Flores Bellver M, Aparicio Domingo S, Zhong X, Barber JR, Joshu CE, Canto-Soler MV, Eberhart CG, Heaphy CM. A unique telomere DNA expansion phenotype in human retinal rod photoreceptors associated with aging and disease. Brain Pathology, 2018.
Heaphy CM, Yoon 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 variability and stromal cell telomere length as prognostic markers for metastasis and death. Cancer Discovery, 2013.
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