The impact of stochastic (epi)mutations on the aging genome

Aging is marked by a degenerative decline in multiple organ systems. One hypothesis regarding the cause of this decline is that it is due to an accumulation of stochastic mutations and/or changes to chromatin state. These (epi)mutations are likely to affect the expression of genes needed for proper cell function. Thus, tissues may experience increasing genomic/epigenomic heterogeneity and the associated individual changes in gene expression may lead to loss of tissue function and degeneration. The use of stem cells to repair and regenerate deteriorated tissues and organs is among the promising therapies for degenerative diseases of aging. However, the promise of this approach depends critically on understanding the mechanisms that stem cells use for evading the errors in DNA sequence and chromatin state that occur with time. The focus of my post-doctoral research is to test the hypothesis that DNA damage and repair can perturb the epigenome and to determine whether stem cells are better at avoiding genomic and epigenomic drift than their differentiated derivatives. My approach will be to evaluate stochastic (epi)mutations at the single cell level. I will induce specific DNA double strand breaks in stem cells and their differentiated progeny and investigate the chromatin state and expression of genes around the break. I will develop and apply cutting-edge single cell assays to understand the link between stochastic (epi)mutations and cell function. Further, we will provide for the first time detailed information about the impact of stochastic (epi)genomic alterations in different cell types (adult and embryonic stem cells, differentiated cells, induced pluripotent stem cells). This knowledge will be extremely valuable for understanding to what extent stochastic (epi)genomic damage is a problem in biomedicine and whether it will be possible to develop strategies for stabilizing the (epi)genome.

Blog post written by Esther Napolitano appears April 9th on the blog of Memorial Sloan Kettering Cancer Center www.mskcc.org/blogTitle: Outsmarting Cancer's Survival Skills The development of targeted therapies is a major leap forward in the treatment of people with solid tumors. Unfortunately, the therapeutic effects of these personalized therapies which are selected based on the biology of an individual's tumor are usually temporary. The vast majority of cancers treated with targeted therapy ultimately become resistant to treatment, stop shrinking, and eventually progress. New research led by investigators at Memorial Sloan Kettering and recently published in the journal Nature gives insight into how melanoma and lung cancer cells that initially respond to targeted therapy develop drug resistance. The study also identifies potential treatment strategies that may delay or prevent tumor relapse in people with these types of cancer.Understanding the Nature of the Enemy For years, researchers have puzzled over the mechanisms that allow cancer cells to evade targeted therapy and continue to grow. Previous studies have identified, in piecemeal fashion, individual factors that can diminish the impact of a therapy. However, efforts to target those single mechanisms and disable their function have only marginally improved the long-term effectiveness of targeted treatments. "Our study found that it's not just one factor, but a complex network of mechanisms that are involved in defending the tumor cells against the effects of targeted therapy. These mechanisms are responsible for the patient's ultimate relapse," says the study's lead investigator Anna Obenauf, a research associate in Memorial Sloan Kettering's Cancer Biology and Genetics Program. "Weve shown how previously identified factors work together to stimulate the growth and spread of small sub-populations of tumor cells that are inherently resistant to treatment." How does this happen? "The treated tumor cells release a storm of signals that produces growth factors and activates as many genes as possible," explains Joan Massagué, Director of the Sloan Kettering Institute and senior author of the study. The signals mount an all-out response to shield these drug-resistant tumor cells from pharmacologic attack and aggressively promote their survival and metastasis or spread. Now we know the nature of the enemy and it's putting out all that it's got." Combining Treatments to Outwit Cancer's Survival Skills Using mouse models that were treated with targeted therapy, researchers added a drug that inhibits a specific cell process called the PI3K/AKT/mTOR pathway. Resistance factors activate the pathway to help melanoma and lung cancer cells survive the effects of targeted therapy. This strategy blunted the outgrowth of drug-resistant cancer cells, suggesting that a similar combination of targeted therapies may potentially delay or prevent tumor relapse in patients. "Based on these results, we think that longer-lasting tumor regression may be possible with a combination of treatments that inhibits the genetic abnormalities that drive cancer growth and also targets the common pathway through which some tumor cells act to promote drug resistance and instruct them to survive," notes Dr. Obenauf. "We need to pursue clinical trials that evaluate this and other combinations of treatment approaches," adds Dr. Massagué, who notes that immunotherapy may be an optimal complement to targeted therapy because it's based on boosting the immune system's inherent ability to fight cancer. "It's worth exploring a completely different and innovative approach like immunotherapy, which may be able to finish off the job that the other targeted drugs cannot fully do on their own."