Siyuan Zhang Dee Associate Professor

Translational cancer research: targeting tumor's genetic and epigenetic adaptation to the tumor 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 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?



  • 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:

  • Wang, Q., Guldner, I.H., Golomb, S.M., Sun, L., Harris, J., 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.
  • 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.
  • Rodriguez, K.X., Howe, E.N., Bacher, E.P., Burnette, M., Meloche, J.L., Meisel, J., Schnepp, P., Tan, X., Chang, M., Zartman, J. *, Zhang, S.*, Ashfeld, B.L. *, (2019). Combined Scaffold Evaluation and Systems-Level Transcriptome-Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes. ChemMedChem.  *:co-corresponding authors
  • 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. Development. 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. Biomaterials170, 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. Feb 16;46(3):e14. 
  • Schnepp, P.M., Lee, D., Guldner, I.H., 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. Jun 1;77(11):2844-2856.
  • Casey, J., Yue, X., Nguyen, 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.  Biomedical Materials Mar 15;12(2):025009. [IF: 2.469]
  • Zellmer, V.R., Schnepp, P.M., Fracci S., Tan, X., Howe E.N., and Zhang, S.   (2017) Tumor-induced Stromal STAT1 Accelerates Breast Cancer via Deregulating Tissue Homeostasis, Mol. Cancer Res. May;15(5):585-597 [IF: 4.974]
  • Guldner, I.H., Yang, L., Cowdrick, K.R., Wang, Q., Alvarez Barrios, W.V. , Zellmer, V.R., Zhang, Y., Host, M.t, Liu, F., Chen, D.Z., Zhang, S. (2016). An Integrative Platform for Three-dimensional Quantitative Analysis of Spatially Heterogeneous Metastasis Landscapes. Sci Report. Apr 12;6:24201. [IF: 4.259]
  • Narciso, C., Cowdrick, K.R. *, Zellmer, V.R., Brito-Robinson, T., Brodskiy, P., Hoelzle, D.J., Zhang, S. #, Zartman J. (2016), On-chip three-dimensional tissue histology for microbiopsies. Biomicrofluidics, v.10, 2016, p. 021101. [IF:2.535] (# co-corresponding authors)
  • Mason, J.A., Davison-Versagli, C.A., Leliaert, A.K., Pape, D.J., McCallister, C, Zuo, J, Durbin, S.M., Buchheit, C.L., Zhang, S., Schafer Z.T. (2016). Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells. Cell Death and Differentiation. Aug;23(8):1271-82. [IF: 8.339]  
  • Rayavarapu, R.R., Heiden, B., Pagani, N., Shaw, M.M., Shuff, S., Zhang, S., and Schafer, Z.T. (2015). The role of multicellular aggregation in the survival of ErbB2-positive breast cancer cells during extracellular matrix detachment. J. Biol. Chem. 290, 8722–8733. [IF: 4.125]
  • 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(7576), 100-4. (# co-first authors) [IF: 40.137]
  • Guldner, I.H., Zhang, S. (2015). A Journey to Uncharted Territory: New Technical Frontiers in Studying Tumor-Stromal Cell Interactions. Integrative Biology 7(2):153-61. [IF: 3.252]
  • Zellmer, V.R., Zhang, S. (2014). Evolving Concepts of Tumor Heterogeneity. Cell & Bioscience. 4:69. [IF: 3.294]
  • Zhang, S., Huang, W.C., Zhang, L., Zhang, C., Lowery, F.J., Ding, Z., Guo, H., Wang, H., Huang, S., Sahin, A.A., Aldape, K.D., Steeg, P.S., Yu, D. (2013). Src Family Kinases as Novel Therapeutic Targets to Treat Breast Cancer Brain Metastases. Cancer Res. 73, 5764–5774. [IF: 9.122]
  • 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.  [IF: 29.886]
  • 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.  [IF: 9.619]
  • 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. [IF: 4.057]