The primary focus of the Meeker lab research activities for the last 2 decades has been on cancer-associated abnormalities in telomere biology. Telomeres are tracts of repetitive DNA located at chromosomal termini and bound by a protein complex known as shelterin. Our earlier discoveries provided significant supporting data for the concept that telomere abnormalities play important roles in human cancer, including both cancer initiation and disease progression. For example, using a novel slide-based telomere-specific FISH assay we developed for determining telomere lengths directly in preserved archival patient tissue samples, we found that the vast majority of pre-malignant carcinoma lesions harbor severe telomere shortening; thus, this telomere abnormality arises very early during the process of tumorigenesis - likely contributing significantly to malignant transformation via chromosomal instability due to telomere dysfunction.
Another provocative discovery is the finding of widespread telomere shortening specifically in benign-appearing breast ductal epithelial cells in normal adult women. This surprising observation may be linked to hormone-dependent, cyclical waves of proliferation and involution in this particular cell population; perhaps helping to explain why it is these cells in particular are at such high risk for malignant transformation. We are currently exploring this further to see if breast epithelial telomere length may represent a useful biomarker for predicting an individual’s future risk of developing breast cancer.
Regarding telomere length as a potential cancer biomarker, we recently found that that tissue-based telomere length measurements were significantly associated with prostate cancer patients’ clinical outcome (cancer-specific death). Based on these results, we developed and validated an automated assay for telomere quantification and have validated this biomarker in additional independent prostate cancer cohorts, with an eye towards eventual clinical implementation.
Another focus of the lab is on telomere maintenance in cancer. Cancer cells typically have very short telomeres maintained via one of two mechanisms. The first of these is the inappropriate expression of the telomere synthesizing enzyme, telomerase. The second is via 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 which undergo inactivating mutations in ALT-positive cancers. Currently, we are working to understand how these ALT-suppressors function at the molecular level. To this end, we utilized the CRISPR-Cas9 system to cleanly delete these genes in various cell lines and monitored their effects on telomeres as cells transit from a non-ALT state to an ALT-positive state. We are now using these non-ALT/ALT parental versus knock out clones as a model system for drug screening efforts to identify agents that will selectively kill ALT-positive cancer cells. If successful, this could have potentially important therapeutic applications, as our work indicates that the ALT telomere maintenance mechanism is only found in cancer cells, and never in normal cells; thus, agents targeting this pathway could potentially have limited side-effects on normal cells.
Telomere loss in non-malignant cells can lead to permanent cell cycle exit, a phenomenon known as cellular senescence. Recently we have begun to explore the potential role for senescent cells as cancer-promoting agents in human tissues. In this regard, we are assessing whether the prevalence and/or phenotype of senescent prostate stromal cells 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. Interestingly, agents have recently been identified that may selectively eliminate senescent cells (“senolytics”) and we are beginning to test the idea that such agents may serve as cancer preventive or therapeutic agents in human cancer.
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 PubMed PMID: 30226859.
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. Nat Commun. 2018 PubMed PMID: 29802247.
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 Pathol. 2018 PubMed PMID: 29668072.
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 Discov. 2013 PMID: 23779129.
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 PMID: 21719641.