Siyuan Zhang Dee Associate Professor

Translational cancer research: targeting co-evolution of tumor and tumor immune microenvironment
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 into the role of the 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 the cellular and subcellular level. We established a single cell-based RNA-seq pipeline (CITE-seq), which enables us to map single-cell level transcriptome dynamics and immune cell surface markers simultaneously during the early tumor development and metastatic colonization stage. Using state-of-the-art techniques and classical animal tumor models, we explore in-depth molecular mechanisms of tissue dynamics during early tumor development, drug resistance, and metastasis colonization. Based on our pre-clinical mechanistic 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:

  1. 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?
  2. How does a heterogeneous tumor respond to environmental stress, such as drug treatment? How does tumor microenvironment prime “seemingly” normal tissue niche and promote accelerated tumor development and metastatic outgrowth in the brain?
  3. Can we systematically delineate tumor and tumor microenvironment genetic landscape in situ? 
Zhang Siyuan Figure


  • Associate Professor, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 2018-Present
  • Assistant Professor, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 2012-2018
  • 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:

  • Golomb SM, Guldner IH, Zhao A, Wang Q, Palakurthi B, Aleksandrovic EA, Lopez J, Lee WS, Yang K, Zhang S. Multi-modal single cell analysis reveals brain immune landscape plasticity during aging and gut microbiota dysbiosis. Cell Reports 2020 Dec 1; 33(9): 108438 [Full text]
  • Guldner, I.H., Wang, Q., Yang, L., Golomb, S.M., Zhao, A., Lopez, J.A., Brunory, A., Howe, E.N., Zhang, Y., Palakurthi, B., Barron, M., Gao, H., Xuei, X., Liu, Y., Li, J., Chen, D.Z., Landreth, G.E., Zhang, S.. 2020. CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10. Cell 2020 Nov 25;183(5):1234-1248.e25. doi: 10.1016/j.cell.2020.09.064.
  • Wang, S., Raybuck, A., Shiuan, E., Cho, S.H., Wang, Q., Brantley-Sieders, D.M., Edwards, D., Allaman, M.M., Nathan, J., Wilson, K.T., DeNardo, D., Zhang, S., Cook, R., Boothby, M., Chen, J., 2020. Selective inhibition of mTORC1 in tumor vessels increases antitumor immunity. JCI Insight 5.
  • Howe, E.N., Burnette, M.D., Justice, M.E., Schnepp, P.M., Hedrick, V., Clancy, J.W., Guldner, I.H., Lamere, A.T., Li, J., Aryal, U.K., D’Souza-Schorey, C., Zartman, J.J., Zhang, S., 2020. Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth. Nat. Commun. 11, 3017.
  • Ni, Y., Schmidt, K.R., Werner, B.A., Koenig, J.K., Guldner, I.H., Schnepp, P.M., Tan, X., Jiang, L., Host, M., Sun, L., Howe, E.N., Wu, J., Littlepage, L.E., Nakshatri, H., Zhang, S., 2019. Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer. Nat. Commun. 10, 2860.
  • Wang, Q., Guldner, I.H., Golomb, S.M., Sun, L., Harris, J.A., Lu, X., Zhang, S., 2019. Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer. Nat. Commun. 10, 1–12.
  • Zhang, Y., Nichols, E.L., Zellmer, A.M., Guldner, I.H., Kankel, C., Zhang, S., Howard, S.S., Smith, C.J., 2019. Generating intravital super-resolution movies with conventional microscopy reveals actin dynamics that construct pioneer axons. Dev. Camb. Engl. 146.
  • Yue, X., Nguyen, T.D., Zellmer, V., Zhang, S., Zorlutuna, P., 2018. Stromal cell-laden 3D hydrogel microwell arrays as tumor microenvironment model for studying stiffness dependent stromal cell-cancer interactions. Biomaterials 170, 37–48.
  • Barron, M., Zhang, S., Li, J., 2018. A sparse differential clustering algorithm for tracing cell type changes via single-cell RNA-sequencing data. Nucleic Acids Res. 46, e14.
  • Schnepp, P.M., Lee, D.D., Guldner, I.H., O’Tighearnaigh, T.K., Howe, E.N., Palakurthi, B., Eckert, K.E., Toni, T.A., Ashfeld, B.L., Zhang, S., 2017. GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment. Cancer Res. 77, 2844–2856.
  • Zellmer, V.R., Schnepp, P.M., Fracci, S.L., Tan, X., Howe, E.N., Zhang, S., 2017. Tumor-induced Stromal STAT1 Accelerates Breast Cancer via Deregulating Tissue Homeostasis. Mol. Cancer Res. MCR 15, 585–597.
  • Casey, J., Yue, X., Nguyen, T.D., Acun, A., Zellmer, V.R., Zhang, S., Zorlutuna, P., 2017. 3D hydrogel-based microwell arrays as a tumor microenvironment model to study breast cancer growth. Biomed. Mater. Bristol Engl. 12, 025009.
  • Guldner, I.H., Yang, L., Cowdrick, K.R., Wang, Q., Barrios, W.V.A., Zellmer, V.R., Zhang, Y., Host, M., Liu, F., Chen, D.Z., Zhang, S., 2016. An Integrative Platform for Three-dimensional Quantitative Analysis of Spatially Heterogeneous Metastasis Landscapes. Sci. Rep. 6, 24201.
  • Zhang, L.*, Zhang, S.*, Yao, J., Lowery, F.J., Zhang, Q., Huang, W.-C., Li, P., Li, M., Wang, X., Zhang, C., Wang, H., Ellis, K., Cheerathodi, M., McCarty, J.H., Palmieri, D., Saunus, J., Lakhani, S., Huang, S., Sahin, A.A., Aldape, K.D., Steeg, P.S., Yu, D., 2015. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104.  * co-1st authors.
  • 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., Sahin, A.A., Esteva, F.J., Hortobagyi, G.N., Yu, D., 2011. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat. Med. 17, 461–469.