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 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 these cells in particular are at such high risk for 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 patient clinical outcome (cancer-specific death). Based on these results, we are developing and validating an automated assay for telomere quantification and are validating this biomarker in additional independent cohorts, with an eye towards eventual clinical implementation. Another focus of the lab is on telomere maintenance in cancer. Although cancer cells typically have very short telomeres, ultimately they maintain their telomeres 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 genes associated with the ALT phenotype in human cancer - ATRX and DAXX; two chromatin remodeling genes 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 are utilizing the CRISPR-Cas9 system to cleanly delete these genes in various cell lines in order to monitor their effects on telomeres as cells transit from a non-ALT state to an ALT-positive state. Furthermore, the generation of non-ALT/ALT parental versus knock out clones provide a key model system for drug screening efforts in an attempt 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.
Koschmann C, Calinescu AA, Nunez FJ, Mackay A, Fazal-Salom J, Thomas D, Mendez F, Kamran N, Dzaman M, Mulpuri L, Krasinkiewicz J, Doherty R, Lemons R, Brosnan-Cashman JA, Li Y, Roh S, Zhao L, Appelman H, Ferguson D, Gorbunova V, Meeker A, Jones C, Lowenstein PR, Castro MG. ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Sci Transl Med. 2016 PubMed PMID: 26936505.
Hurwitz LM, Heaphy CM, Joshu CE, Isaacs WB, Konishi Y, De Marzo AM, Isaacs SD, Wiley KE, Platz EA, Meeker AK. Telomere length as a risk factor for hereditary prostate cancer. Prostate. 2014 PubMed PMID: 24285042.
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 PubMed PMID: 23779129.
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 telomere maintenance mechanism in human cancer subtypes. Am J Pathol. 2011 PubMed PMID: 21888887.
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 PubMed PMID: 21719641.