Siyuan Zhang Dee Assistant Professor

Siyuan Zhang

Research Interests:

Exploring the co-evolution between tumor cells and tumor microenvironment is a central theme of my laboratory. We aim to tackle the overarching challenge of studying early tumor/metastasis development in situ and gain unprecedented mechanistic insights of the role of tumor microenvironment during cancer progression in its native pathophysiological microenvironment.

We are integrating innovative approaches to faithfully model and investigate the dynamic interaction between a tumor and its tumor microenvironment at the single cell level. We have developed intravital multiphoton imaging and lipid clearing-based whole tissue imaging techniques, which allow us to explore the spatiotemporal dynamics of tumor and tumor microenvironment in situ at cellular and subcellular level. We have also established a single cell-based RNA-seq pipeline, which enables us to map single cell level transcriptome dynamics at the early tumor development and metastatic colonization stage. Using state-of-the-art techniques and classical animal tumor models, we are poised to reveal in-depth molecular mechanisms of tissue dynamics during early tumor development, drug resistance and metastasis colonization. Base on our pre-clinical findings, we conduct pre-clinical testing of novel combinatorial therapies to overcome drug resistance and prevent tumor metastasis.

Three specific research themes in my laboratory are:

  • What are the critical genomic/transcriptomics changes at the first moment of metastatic seeding and colonization? Can we exploit those changes as novel therapies to prevent metastatic outgrowth?
  • How does a heterogeneous tumor respond to environmental stress, such as drug treatment? How does tumor microenvironment prime “seemingly” normal tissue and promote accelerated tumor development and acquired drug resistance?
  • Can we systematically delineate tumor and tumor microenvironment genetic landscape in situ?



  • Assistant Professor, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 2012-Present
  • Adjunct Assistant Professor, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 2012-Present
  • Instructor, Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 2011-2012
  • Postdoctoral Fellow, Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 2007-2011
  • Research Associate, Department of Community, Occupational and Family Medicine National University of Singapore, Republic of Singapore 2005-2006
  • Ph.D., Cancer Biology, National University of Singapore, Singapore 2001-2005
  • M.D., Medicine, Peking University, Beijing, China 1993-1998


Recent Papers:

  • Zhang L*, Zhang S*, Yao J, Lowery FJ, Zhang Q, Huang WC, Li P, Li M, Wang X, Zhang C, Wang H, Ellis K, Cheerathodi M, McCarty JH, Palmieri D, Saunus J, Lakhani S, Huang S, Sahin AA, Aldape KD, Steeg PS, Yu D. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. (2015) Nature. 2015 Oct 19. doi: 10.1038/nature15376. [Epub ahead of print] (*co-first author)
  • Guldner, I.H., Zhang, S.. A Journey to Uncharted Territory: New Technical Frontiers in Studying Tumor-Stromal Cell Interactions. (2015) Integrative Biology 7(2):153-61.
  • Zellmer, V.R. , Zhang, S.. Evolving Concepts of Tumor Heterogeneity. (2014) Cell & Bioscience. 4:69
  • Zhang, S., Huang, W.-C., Zhang, L., Zhang, C., Lowery, F.J., Ding, Z., Guo, H., Wang, H., Huang, S., Sahin, A.A., et al. (2013). Src Family Kinases as Novel Therapeutic Targets to Treat Breast Cancer Brain Metastases. Cancer Res. 73, 5764–5774.
  • Zhang, S., and Yu, D. (2012). Targeting Src family kinases in anti-cancer therapies: turning promise into triumph. Trends Pharmacol. Sci. 33, 122–128.
  • Zhang, S., Huang, W.-C., Li, P., Guo, H., Poh, S.-B., Brady, S.W., Xiong, Y., Tseng, L.-M., Li, S.-H., Ding, Z., et al. (2011). Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat. Med. 17, 461–469.
  • Zhang, S., and Yu, D. (2010). PI(3)king apart PTEN’s role in cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 16, 4325–4330.
  • Esteva, F.J., Guo, H., Zhang, S., Santa-Maria, C., Stone, S., Lanchbury, J.S., Sahin, A.A., Hortobagyi, G.N., and Yu, D. (2010). PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am. J. Pathol. 177, 1647–1656.
  • Wu, Y.-T., Zhang, S., Kim, Y.-S., Tan, H.-L., Whiteman, M., Ong, C.-N., Liu, Z.-G., Ichijo, H., and Shen, H.-M. (2008). Signaling pathways from membrane lipid rafts to JNK1 activation in reactive nitrogen species-induced non-apoptotic cell death. Cell Death Differ. 15, 386–397.
  • Zhang, S., Lin, Y., Kim, Y.-S., Hande, M.P., Liu, Z.-G., and Shen, H.-M. (2007). c-Jun N-terminal kinase mediates hydrogen peroxide-induced cell death via sustained poly(ADP-ribose) polymerase-1 activation. Cell Death Differ. 14, 1001–1010.
  • Zhang, S., Li, Z., Wu, X., Huang, Q., Shen, H.-M., and Ong, C.-N. (2006). Methyl-3-indolylacetate inhibits cancer cell invasion by targeting the MEK1/2-ERK1/2 signaling pathway. Mol. Cancer Ther. 5, 3285–3293.