Alan Meeker
Telomere biology and maintenance in cancer
Associate Professor
Department of Pathology
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.
Topic Areas
Selected Publications
- Mori JO, Elhussin I, Brennen WN, Graham MK, Lotan TL, Yates CC, De Marzo AM, Denmeade SR, Yegnasubramanian S, Nelson WG, Denis GV, Platz EA, Meeker AK, Heaphy CM. Prognostic and therapeutic potential of senescent stromal fibroblasts in prostate cancer. Nature Reviews Urology, 2024.
- Heaphy CM, Joshu CE, Barber JR, Davis C, Lu J, Zarinshenas R, Giovannucci E, Mucci LA, Stampfer MJ, Han M, De Marzo AM, Lotan TL, Platz EA, Meeker AK. The prostate tissue-based telomere biomarker as a prognostic tool for metastasis and death from prostate cancer after prostatectomy. Journal Pathology Clinical Research, 2022.
- Zhan D, Ma D, Wei S, Lal B, Fu Y, Eberhart C, Laterra J, Ying M, Li Y, Meeker A, Lopez-Bertoni H, Xia S. Monoallelic IDH1 R132H Mutation Mediates Glioma Cell Response to Anticancer Therapies via Induction of Senescence. Molecular Cancer Research, 2021.
- Joshu CE, Heaphy CM, Barber JR, Lu J, Zarinshenas R, Davis C, Han M, Lotan TL, Sfanos KS, De Marzo AM, Meeker AK, Platz EA. Obesity is Associated with Shorter Telomere Length in Prostate Stromal Cells in Men with Aggressive Prostate Cancer. Cancer Prevention Research, 2021.
- 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.