Major finding: Reactivation of telomerase in cells with telomere dysfunction drives metastasis.

Clinical Relevance: A murine bone-metastasis gene signature has prognostic value in humans.

Impact: This study provides genetic evidence that telomerase reactivation drives cancer.

It has long been hypothesized that aberrant reactivation of telomerase is a key step in the development of cancer, but this theory has lacked genetic proof in vivo. Ding and colleagues evaluated the role of telomerase reactivation in a genetically engineered mouse model of prostate cancer by crossing telomerase reverse transcriptase (Tert) null alleles or Cre recombinase-inducible Tert knock-in alleles into mice with p53 and Pten conditional knockout alleles that specifically express Cre in the prostate epithelium at sexual maturity (5 to 7 weeks of age). After 3 to 4 generations of inbreeding, these mice displayed characteristic features of telomere dysfunction (e.g., reduced body weight, organ atrophy, and increased apoptosis in proliferative tissues). The Pten/p53-deficient mice with wild-type telomerase developed high-grade prostate intraepithelial neoplasia (PIN) by 9 weeks of age, which progressed to adenocarcinoma in 100% of mice by 24 weeks. All of the late-generation Tert-null, Pten/p53-deficient mice also developed PIN by 9 weeks, but most tumors did not progress within 24 weeks, indicating that telomere dysfunction can initiate oncogenesis but is insufficient for cancer progression. However, in 100% of the late-generation Tert-knock-in mice, which had dysfunctional telomeres before reactivation of telomerase, the PIN that initiated by 9 weeks progressed to large, lethal tumors capable of metastasizing to the lumbar spine. These tumors had recurring genetic abnormalities that were syntenic to regions with frequent copy-number aberrations in human prostate cancer, and a group of the affected genes could robustly stratify human patients according to risk of recurrence. Together, these findings provide strong evidence that telomerase reactivation subsequent to telomere dysfunction is an important mechanism of tumorigenesis and identify potential therapeutic targets for prostate cancer treatment as well as a prognostic tool to distinguish aggressive prostate cancers from those less likely to progress.

Ding Z, Wu CJ, Jaskelioff M, Ivanova E, Kost-Alimova M, Protopopov A, et al. Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell 2012;148:1–12.