Research Focus
Chromosomes carry the genetic blueprint of human life which tells our cells how to function. One of the most common genetic alterations in cancer is oncogene amplification. Oncogenes are genes known to promote cancer formation and growth. Instead of two copies, a cancer cell might have 10, 20, 30, or even more copies of an oncogene, which promotes unrestrained proliferation. However, many amplified oncogenes are not physically located where the genomic maps indicate. Instead, they frequently jump off the chromosome and amplify as circular extrachromosomal DNA (ecDNA) particles, especially in the most aggressive cancer types, including brain, lung, and breast cancers. Accumulating evidence suggests that ecDNA drives malignant behaviors in cancer cells, such as drug resistance, but our understanding of ecDNA is limited.
The long-term goal of our lab is to understand the functions of ecDNA and how ecDNA is maintained in cancer. We are integrating several approaches (sequencing, cytogenetic profiling with high-resolution imaging, and bioinformatics) to tackle these questions. If we can understand these mechanisms, we can develop specific therapeutic strategies to eliminate ecDNA and target oncogenes that are currently undruggable.
Research Projects
Molecular functions of ecDNA in cancer
Molecular co-dependency of ecDNA in cancer
Molecular functions of ecDNA in cancer
DNA encodes information both in its sequence and its shape. To date, we have obtained clear images of ecDNA, showing its circular configuration and acentric nature. These two features allow ecDNA to increase its copy number rapidly, generating more and more templates for oncogene expression. Furthermore, the random segregation of ecDNA during mitosis boosts the cancer heterogeneity dramatically, freeing cancer from the constrain of Mendelian inheritance to evolve and adapt to the ever-changing microenvironment quickly.
Nonetheless, we still lack the knowledge of how ecDNA impacts the cancer genome, such as transcriptional activity. As a piece of genetic material, ecDNA also serves as a template for gene transcription. However, its small size, high copy number, hyper-accessible chromatin, and spatial localization allow it to freely interact with the cancer genome, including ecDNA–ecDNA and ecDNA–chromosomal DNA interactions. We are interested in characterizing these interactions by integrating modern sequencing and high-resolution imaging approaches to understanding how the unique physical feature and spatial organization of ecDNA act on cancer transcriptome and cellular behaviors.
Molecular co-dependency of ecDNA in cancer
Oncogenes are frequently amplified on ecDNA, promoting massive oncogene expression due to the high copy number of ecDNAs and their unusually accessible chromatin. Therefore, cancer cells must evolve a set of mechanisms to maintain the ecDNA population and ensure its genetic function, creating ecDNA co-dependencies in cancer. These co-dependent mechanisms include ecDNA replication, transcription, epigenetic modification, and repair. However, our understanding of how cancer weaves these co-dependencies is still limited.
To uncover this mystery, we use whole-genome sequencing, epigenetic profiling, 3D genome capturing, and computational pipelines to characterize the ecDNA amplicon architecture, as well as its genetic and epigenetic features. We aim to extract this series of information to understand how ecDNA replicates, transcribes, and repairs, as well as how ecDNA’s unique accessibly chromatin and 3D topology impact these processes. We also use high-resolution imaging and protein mass spectrometry to characterize the core components responsible for ecDNA maintenance. We hope to leverage this knowledge to develop novel strategies to specifically target ecDNA in cancer and improve the current therapeutic regime.
About Dr. Wu
Dr. Sihan Wu has an extensive background in cancer genetics and genomics. After graduating from Sun-Yat-sen University (SYSU), where he majored in biotechnology in the Life Science School, he obtained his Ph.D. at the Zhongshan School of Medicine at SYSU. His doctoral research focused on how genetic alterations contribute to brain tumor development. His work led to the discovery that dysregulation of non-coding microRNAs contributes to the development of glioblastoma. After receiving his Ph.D., he initiated postdoctoral research at the Ludwig Institute for Cancer Research at the University of California, San Diego, under Dr. Paul Mischel’s mentorship. There he studied the structure and function of extrachromosomal DNA (ecDNA) in cancer, uncovering its circular shape and the functional impact of its unique physical conformation.
In 2021, Dr. Wu joined the faculty of Children’s Medical Center Research Institute at UT Southwestern as an assistant professor and became a Cancer Prevention and Research Institute of Texas (CPRIT) scholar. He holds a secondary appointment in pediatrics.
Selected Publications
Chen, P.B., Fiaux, P.C., Zhang, K., Li, B., Kubo, N., Jiang, S., Hu, R., Rooholfada, E., Wu, S., Wang, M., Wang, W., McVicker, G., Mischel, P.S., and Ren, B. (2022). Systematic discovery and functional dissection of enhancers needed for cancer cell fitness and proliferation. Cell Rep. 41, 111630. (PubMed)
Lange, J.T., Rose, J.C., Chen, C.Y., Pichugin, Y., Xie, L., Tang, J., Hung, K.L., Yost, K.E., Shi, Q., Erb, M.L., Rajkumar, U., Wu, S., Taschner-Mandl, S., Bernkopf, M., Swanton, C., Liu, Z., Huang, W., Chang, H.Y., Bafna, V., Henssen, A.G., Werner, B., and Mischel, P.S. (2022). The evolutionary dynamics of extrachromosomal DNA in human cancers. Nat Genet. Epub ahead of print. (PubMed)
Hung, K.L., Yost, K.E., Xie, L., Shi, Q., Helmsauer, K., Luebeck, J., Schöpflin, R., Lange, J.T., Chamorro González, R., Weiser, N.E., Chen, C., Valieva, M.E., Wong, I.T., Wu, S., Dehkordi, S.R., Duffy, C.V., Kraft, K., Tang, J., Belk, J.A., Rose, J.C., Corces, M.R., Granja, J.M., Li, R., Rajkumar, U., Friedlein, J., Bagchi, A., Satpathy, A.T., Tjian, R., Mundlos, S., Bafna, V., Henssen, A.G., Mischel, P.S., Liu, Z., and Chang, H.Y. (2022). ecDNA hubs drive cooperative intermolecular oncogene expression. Nature. 600, 731-736. (PubMed)
Wu, S., Bafna, V., Chan,g H. Y., and Mischel, P. S. (2022). Extrachromosomal DNA: An Emerging Hallmark in Human Cancer. Annu. Rev. Pathol. Mech. Dis.17, 367-386. (PubMed)
Wu, S., Bafna, V., and Mischel, P. S. (2021). Extrachromosomal DNA (EcDNA) in Cancer Pathogenesis. Curr Opin Genet Dev. 66, 78–82. (PubMed)
Kim, H., Nguyen, N.-P., Turner, K., Wu, S., Gujar, A. D., Luebeck, J., Liu, J., Deshpande, V., Rajkumar, U., Namburi, S., Amin, S. B., Yi, E., Menghi, F., Schulte, J. H., Henssen, A. G., Chang, H. Y., Beck, C. R., Mischel, P. S., Bafna, V., and Verhaak, R. G. W. (2020). Extrachromosomal DNA Is Associated with Oncogene Amplification and Poor Outcome across Multiple Cancers. Nat Genet. 52, 891–897. (PubMed)
Cai, J., Liu, W., Wong, C. W., Zhu, W., Lin, Y., Hu, J., Xu, W., Zhang, J., Sander, M., Wang, Z., Dan, J., Zhang, J., Liu, Y., Guo, L., Qin, Z., Liu, X., Liu, Y., Yan, G., Wu, S., and Liang, J. (2020). Zinc-Finger Antiviral Protein Acts as a Tumor Suppressor in Colorectal Cancer. Oncogene 39, 5995–6008. (PubMed)
Bi, J., Chowdhry, S., Wu, S., Zhang, W., Masui, K., and Mischel, P. S. (2020). Altered Cellular Metabolism in Gliomas — an Emerging Landscape of Actionable Co-Dependency Targets. Nat Rev Cancer. 20, 57–70. (PubMed)
Wu, S., Turner, K. M., Nguyen, N., Raviram, R., Erb, M., Santini, J., Luebeck, J., Rajkumar, U., Diao, Y., Li, B., Zhang, W., Jameson, N., Corces, M. R., Granja, J. M., Chen, X., Coruh, C., Abnousi, A., Houston, J., Ye, Z., Hu, R., Yu, M., Kim, H., Law, J. A., Verhaak, R. G. W., Hu, M., Furnari, F. B., Chang, H. Y., Ren, B., Bafna, V., and Mischel, P. S. (2019). Circular EcDNA Promotes Accessible Chromatin and High Oncogene Expression. Nature 575, 699–703. (PubMed)
