Sandy Chang, M.D., Ph.D.

Telomeres are G-rich repeat sequences that cap the ends of most eukaryotic chromosomes and serve to protect natural DNA ends from being recognized as double-stranded breaks. The synthesis and maintenance of telomeric repeats are mediated by telomerase, a specialized ribonucleoprotein complex consisting of both RNA and protein components. In the absence of telomerase, progressive telomere shortening triggers the activation of the p53 and Rb tumor suppressor pathways, which provide signals for replicative senescence. Disruption of p53 and RB can extend the replicative potential, however, continuous cellular proliferation drives further telomere shortening, culminating in telomere erosion and entry into a crisis phase of rampant genomic instability and cell death. Both senescence and crisis are potent tumor suppressor mechanisms. Therefore, human cancer cells must activate telomere maintenance programs in order to proliferate indefinitely. Reactivation of telomerase is observed in the majority of human cancers, and is a critical event that promotes sustained tumor cell proliferation by removing the short telomeric barriers necessary for tumor progression.

My research interests lie in understanding the role and regulation of telomeres and telomerase in cancer pathogenesis and the aging process. We are usng the telomerase knockout mouse as a model system to understand the role of telomeres in normal development, aging and cancer progression in vivo. This mouse model has revealed that telomeres play an essential role in chromosomal and genomic stability, that telomere erosion elicits very complex cellular responses which ultimately compromises organismal fitness, and that telomere function is intimately connected to cancer biology and aging. In addition, we have also learned that telomere dysfunction, coupled with p53 mutation, promotes the formation of carcinomas, the most dominant cancer type in elderly individuals. We are currently using molecular cytogenetic techniques such as Spectral Karyotyping to characterize the genomes of these carcinomas. Using transgenic and knockout technologies, we will generate additional mouse models of human carcinomas which we expect to faithfully recapitulate the telomere dynamics observed in human cancers.

We are also characterizing a mouse model of premature aging. We have generated compound knockout mice bearing deletions in both the telomerase and Werner gene. In humans, mutations of the Wrn gene leads to Werner Syndrome, a rare autosomal recessive disorder affecting approximately 10 per million individuals. Patients are normal until adolescence, when they develop clinical features of premature aging. Our working hypothesis is that loss of Wrn in the setting of short telomeres results in genomic instability and premature aging in vivo, and we have data supporting this hypothesis. Our long-term goal is to understand pathways and molecules that may be perturbed in the setting of genomic instability, and how these pathways impact on mammalian organismal aging and cancer.

Recent publications

Wu, L, Multani, AS, He, H, Cosme-Blanco, W, Deng, Y, Deng, JM, Bachilo, O, Pathak, S, Tahara, H, Bailey, SM, Deng, Y, Behringer, RR and Chang, S. (2006) Pot1 Deficiency Promotes Recombination at Telomeres, Chromosomal Instability, and Malignant Transformation. Under review at Cell.
Haines, BB, Ryu, CJ, Chang, S, Protopopov, A, Luch, A, Kang, YH, Draganov, DD, Fragoso, MF, Paik, SG, Hong, HJ, DePinho, RA, and Chen, J. (2006) Persistent RAG Activity Is Associated with Characteristic Chromosome Translocations and Amplifications in Lymphomas. Cancer Cell, 9(2):109-120.
Laud, PA, Bailey, SM, Multani, AM, Kingsley, C, Wu, L, Pathak, S, and DePinho, RA and Chang, S. (2005) Elevated Telomere-telomere Recombination Correlates with Increased Cellular Immortalization and Transformation in G5 mTerc-/- Wrn-/- Mouse Cells. Genes and Development, 19(21):2560-2570.
Hingorani, SR, Wang, L, Multani, AS, Combs, C, Deramaudt, TB, Hruban, RH, Rustgi, AK, Chang, S and David A. Tuveson. (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability in the absence of telomere erosion and define a unique genetic pathway to metastatic pancreatic ductal adenocarcinoma. Cancer Cell 7(5):469-483.
Liu G, Parant JM, Chau P, Lang G. El-Naggar AK, Multani A, Chang S, Lozano G. (2004) Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in p53 mutant mice. Nature Genetics, 36:63-68.
Tuveson, DA, Shaw, A, Willis, NA, Silver, DP, Jackson, EL, Chang, S, Mercer, KL, Grochow, R, Hock, H, Crowley, D, Hingorani, SR, Zaks, T, King, C, Jacobetz, MA, Bronson, RT, Orkin, SA, DePinho, RA, & Jacks, T. (2004) Endogenous oncogenic K-rasG12D stimulates proliferation and initiates neoplasia. Cancer Cell, 5(4):375-387.
Akli, S., Zheng, P., Multani, A., Wingate, H, Pathak, S, Zhang, N, Tucker, SL, Chang, S and Keyomarsi, K. (2004) The tumor specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27 and anti-estrogens in breast cancer. Cancer Research, 64(9):3198-3208.
Chang, S*, Multani, A., Cabrera, N., Naylor, M.L., Laud, P., Lombard, D., Pathak, S., Guarente, L. and DePinho, R.A.* (2004) Essential Role of Limiting Telomeres in the Pathogenesis of Werner Syndrome. Nature Genetics, 36(8); 877-882. *co-corresponding authors
Chang, S. and DePinho, R.A. (2002) Telomerase Extracurricular Activities. PNAS; 99: 12520-12522.
Chang, S., Khoo, C., and DePinho, RA. (2001) Modeling Chromosomal instability and epithelial carcinogenesis in the telomerase deficient mouse. Seminars in Oncology 11:227-238.
Chang S, Khoo C, Naylor M, Maser R, DePinho R. (2003) Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. Genes and Development, 17:88-100.
O'Hagan R*, Chang S*, Maser R, Mohan R, Artandi S, Chin L, DePinho R. (2002) Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell; 2:149-152. *equal contribution
Ranganathan, V, Heine, W, Ciccone, DN, Rudolph, KL, Wu, X, Chang, S, Hai, H, Livingston, DM, Resnik, I, Rosen, F, Seemanova, E, Jarolim, P, DePinho, RA, Weaver, DT. (2001) Rescue of a novel telomere length defect of Niijmegen Breakage syndrome cells requires NBS and telomerase catalytic subunits. Current Biol.; 11: 962-966.
Ferguson, DO, Sekiguchi, JM, Chang, S, Frank, KM, Gao, Y, DePinho, RA, Alt, FW. (2000) The nonhomologous end-joining pathway of DNA repair is required for genomic instability and the suppression of translocations. PNAS; 97:6630-3.
Wong K-K, Chang S, Weiler SR, Ganesan S., Chaudhura J, Zhu C., Artandi SE, Rudolph KL, Gottlieb GJ, Chin L, Alt FW, DePinho RA. (2000) Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nature Genet.; 26:85-88.
Artandi S, Chang S, Lee S, Alson, S, Gottlieb G, Chin L., and Depinho R.A. (2000) Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature; 406:641-645.
Rudolph KL, Chang S, Millard M. Schreiber-Agus N. DePinho RA. (2000) Inhibition of experimental liver cirrhosis in mice by telomerase gene therapy. Science; 87:1253-1258.
Rudolph KL, Chang S, Lee H-W, Blasco M, Gottlieb GJ, Greider C, DePinho RA. (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell; 96:701-712.
Chang S, Stacey K, Hume D, Aderem A. (1999) Mechanism of regulation of the MACMARCKS gene in macrophages by bacterial lipopolysaccharide. J. Leu. Res.; 66:528-534.
Myat MM, Chang S, Rodriguez-Boulan E, Aderem A. (1998) Identification of the basolateral targeting determinant of a peripheral membrane protein, MacMARCKS, in polarized cells. Curr. Biol.; 8:677-683.
Chen J, Chang S, Duncan SA, Okano HJ, Fishell G, Aderem A. (1996) Disruption of the MacMARCKS gene prevents cranial neural tube closure and results in anencephaly. Proc. Natl. Acad. Sci. USA; 93:6275-6279.
Chang S, Hemmings HC, Aderem A. (1996) Stimulus-dependent phosphorylation of MacMARCKS, a Protein Kinase C substrate, in nerve termini and PC12 cells. J. Biol. Chem.; 271:1174-1178.
Duke RC, Persechini PM, Chang S, Liu, CC, Cohen JJ, and Young, JDE. (1989) Purified perforin induces target cell lysis but not DNA fragmentation. J. Exp. Med.; 170:1451-1456.
Aksoy S, Williams S, Chang S, Richards FF. (1989) SLACS retrotransposon from Trypanosoma brucei gambiense is similiar to mammalian LINEs. Nuc. Acids Res.; 18: 785-792.
Barksdale WS, Chang S, Hall DS, Ingvarsson, SI, Stelzer, HJ, Wasson, NF, Ziegler, KW. (1984) Discovery that HR 454 is a variable star. Commission 27 of the Int. Astro. Union Info. Bull. Var. Stars.; 2632: 1-2.