Sandy Chang PhD, MD
Associate Professor of Laboratory Medicine and of Pathology; Associate Director, Molecular Diagnostics Laboratory
Mouse models of cancer; DNA damage; Telomere biology
Dr. Chang has a strong track record in implementing tools and techniques, including the use of mouse genetics and cell biology approaches, to address the questions in telomere biology. Dr. Chang has been an active contributor for over adecade in how telomeres, repetitive sequences that cap the ends of eukaryoticchromosomes, protect chromosomal ends from being recognized as damaged DNA. Using mouse knockout technology and cellular/biochemical studies, his laboratory has previouslydemonstrated that single-strand telomere binding proteins protect chromosome ends from initiating a DNA damage response (DDR). In particular, his lab discovered that the Protection of Telomere 1a (Pot1a) protein plays an important role to protect telomeres from engaging an ATR-dependent DDR, which initiates p53 dependent apoptosis and/or cellular senescence. His lab also discovered that Pot1b, the second Pot1 ortholog in the mouse genome, is required for stem cell proliferation. The Pot1b conditional knockout mouse recapitulates many salient features of human bone marrow (BM) failure syndromes, and will be used to understand what roles dysfunctional telomeres play in the pathogenesisof BM failure. The Chang lab is also generating additional novel mouse models to understand mechanistically how dysfunctional telomeres activate apoptotic and/or cellular senescence pathways to suppress hematopoietic stem cell proliferation commonly observed in BM failure.
Extensive Research Description
Dr. Chang’s research program focuses on telomeres,repetitive DNA sequences at the ends of chromosomes critically important forthe maintenance of genome stability. Perturbation of telomere length results intelomere dysfunction, leading to increased genomic instability that can promoteearly aging and cancer development. Dr. Chang’s laboratory was the first togenerate a faithful mouse model of Werner Syndrome (WS). This rare diseasestrikes individuals in their 30s and is marked by the development of agingphenotypes and early onset of cancer.
Dr. Chang found that when WRN deficiency is coupled withtelomere dysfunction, the combination increases genomic instability, prematureaging and increased tumorigenesis. In addition, his findings conclusively demonstratethat telomere status plays an important role in the development of prematureaging pathologies observed in WS patients. With this mouse model, Dr. Chang'slaboratory has also identified common genetic pathways that unify aging and cancerdevelopment. His laboratory was the first to show that WRN plays a criticalrole in preventing telomeres from undergoing aberrant homologous recombination. In the absence of both telomerase and WRN, telomeresreadily undergo homologous recombination to generate long telomeres, activatingan Alternative lengthening of Telomeres (ALT) phenotype that contributes totumor formation. Dr. Chang’s findingsthus shed light on the important link between aging and cancer by suggestingthat WRN plays an important role in both of these processes.
Dr. Chang then went on to decipher the molecular mechanismsof how telomere dysfunction initiates premature aging phenotypes in thelaboratory mouse. Dr. Chang's laboratoryrecently discovered that the POT1 (Protection of Telomere 1) protein is anintegral member of a protein complex that binds to telomeres and is essentialfor the maintenance of telomere stability. Using homologous recombination, hislaboratory conditionally deleted POT 1 from the mouse genome and discoveredthat chromosomes became highly unstable. These results indicate that POT1 isnormally required to suppress genomic instability by preventing the formationof dysfunctional telomeres. Importantly, loss of POT1 potently activates a DNAdamage pathway that results in rapid onset of cellular senescence. In p53 nullcells, this elevated genomic instability promotes malignant transformation andrapid onset of cancer. These important resultssuggest that dysfunctional telomeres could either suppress tumorigenesis byinitiating cellular senescence (in the setting of an intact p53 pathway), orpromote cancer through elevated genomic instability (in the setting of p53deficiency). Dr. Chang is currently using this novel mouse model to explore theroles that cellular senescence play in initiating premature aging phenotypes inhighly proliferative organs, including the intestine and hematopoietic systems.
Dr. Chang then proceeded to address a long standing questionin the telomere field-is cellular senescence capable of suppress tumorigenesis in vivo? While apoptosis clearly has atumor suppressive role in vivo, untilrecently it was not clear whether p53-dependent cellular senescence plays anyrole in tumor suppression in vivo. Usingclever mouse genetics, Dr. Chang’s laboratory generated mouse models withdysfunctional telomeres and a knock-in p53 allele that is able to activatecellular senescence but not apoptosis. His laboratory demonstrated for the first time that activation ofcellular senescence by dysfunctional telomeres in mice potently suppressed tumorinitiation. Interestingly, while these mice did not succumb to cancer, many dieearly from cellular defects resembling advanced aging. These results suggest that initiation oftelomere dysfunction in vivocompromises cellular renewal, resulting in the onset of premature agingphenotypes.
Dr. Chang is currently focusing on how dysfunctionaltelomeres activate the DNA damage pathway, and the mechanisms that repair them.He continues to use novel molecular and biochemical approaches, as well as thegeneration of new mouse models of telomere dysfunction, to address thesequestions.