Many congratulations to Dr. Zhihu (Jeff) Ding and Chang-Jiun (Terrence) Wu for publishing a Cell paper in March, 2012! Dr. Ding and Dr. Wu were post-doctoral fellows at Dana-Farber Cancer Institute, Harvard Medical School. Dr. Ding was the in the laboratory of Dr. DePinho, and Dr. Wu is in the in the laboratory of Dr. Chin.

Photo: Drs. Zhihu (Jeff) Ding 丁志虎 (right) and Ronald A. DePinho (left).

The title of Dr. Ding and Dr. Wu’s recent Cell paper is “Telomerase Reactivation following Telomere Dysfunction Yields Murine Prostate Tumors with Bone Metastases” [Cell. 2012 Mar 2;148(5):896-907. Epub 2012 Feb 16]. Here is the short description of their work:

Telomeres are the “protective caps” at the ends of chromosomes. Telomerase adds specific GGGTTA DNA sequences to telomeres, thereby stabilizing them in cells. However, the role of telomere dysfunction and telomerase reactivation in cancer progression and in generating genomic events that may promote new tumor biological properties in vivo were not well understood. Zhihu Ding (leading author), Chang-Jiun Wu (co-first author), Lynda Chin (senior author), Ronald DePinho (senior author) and their collaborators have now provided genetic evidence that genomic instability caused by an erosion of the protective caps on chromosomes, followed by activation of telomerase that reinforces those caps, allows malignant cells to evade destruction and acquire more deadly characteristics.

To determine the role of telomere dysfunction and telomerase reactivation in cancer progression, the authors generated an inducible telomerase reverse transcriptase (mTert) allele which were crossed onto a mouse model null for Pten and p53 tumor suppressors. Deletion of Pten and p53 in mouse prostate without the telomere dysfunction develop locally invasive, non-metastatic prostate cancer.

The authors found that Pten/p53 null mice with constitutive telomerase deficiency and telomere dysfunction developed precancerous high-grate prostate intraepithelial neoplasia (HPIN) but 60 percent of them did not progress to invasive prostate cancer. Signs of programmed cell death triggered by genetic abnormalities abounded in this group of mice. In contrast, Pten/p53 null mice with telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated lethal bulky tumors tumors, with 5 of 20 mice developing spinal bone metastases that were not observed in the genome-stable mice.

The authors analyzed gene copy number aberrations—genes deleted or amplified—in the mouse prostate tumors with telomerase reactivation in the setting of telomere dysfunction. They found 22 of the 94 copy number alterations involving deletion or amplification of 741 genes identified in mice were similar to those found in human prostate tumors. A focused analysis of gene alterations found in bone metastases pointed to the enrichment of the TGF-β/SMAD4 network. The authors took this finding back to the mouse model with tumor suppressor p53 and Pten knocked out, and they confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression including skeletal metastases. This study establishes, in a genetic manner, that telomerase reactivation in tumor cells experiencing telomere dysfunction provides a mechanism for selection of cooperative events of gene alterations required for full tumor progression.

Finally, the authors looked at a total of14 genes in nine molecular pathways found to be enriched in bone metastasis to see if they were prognostic for recurrence (as measured by PSA levels after surgery) among 140 prostate cancer patients. They found that this 14-gene set was indeed significantly prognostic of biochemical recurrence, which validated the correlative evidence for biological relevance of these gene alterations to human prostate cancers.

These insights have been licensed by Metamark GENETICS, INC. (http://www.metamarkgenetics.com/) through Dana-Farber Cancer Institute in order to generate a test with clinical utility.

If anyone is interested in his research, you can email Dr. Ding directly at zhihu.ding@gmail.com.

Cheers

HMS-CSSA