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:

  • Schnepp, P.M.g, Lee, D. u, Guldner, I.H. g, Palakurthi, B. g, Eckert, K.E. u, Toni, T.A. u, Ashfeld, B.L., Zhang, S. (2017). Brain Metastatic Microenvironment Reshapes Cancer Cell Metabolism through Epigenetic Up-Regulation of Glutamate Decarboxylase 1, Cancer Res.  (accepted)
  • Casey, J., Yue, X., Nguyen, D., Acun, A., Zellmer, V., Zhang, S., Zorlutuna, P (2017). 3D Hydrogel-Based Microwell Arrays As A Tumor Microenvironment Model To Study Breast Cancer Growth. Biomedical Materials (accepted)
  • Zellmer, V.R. g, Schnepp, P.M. g, Fracci S. u, Tan, X. p, Howe E.N. p, and Zhang, S., (2017) Tumor-induced stromal STAT1 signaling deregulates the mammary gland stem cell niche and accelerates breast cancer development, Mol. Cancer Res. (accepted)
  • Yang, L., Zhang, Y., Guldner, I.H. g, Zhang, S., Chen, D.Z. (2016). 3D Segmentation of Glial Cells Using Fully Convolutional Networks and k-Terminal Cut. To be published in Proc. of the 19th International Conference on Medical Image Computing and Computer-Assisted Intervention – MICCAI, October 17-21, 2016.
  • Guldner, I.H. g, Yang, L., Cowdrick, K.R. u, Wang, Q., Alvarez Barrios, W.V. g, Zellmer, V.R. g, 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. Apr 12;6:24201. [IF: 5.578]
  • Narciso, C., Cowdrick, K.R. u, Zellmer, V.R. g, 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:3.357] (* 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: 8.184]
  • Lake, M., Lake, M., Narciso, C., Cowdrick, K.R. u, Storey, T., Zhang, S., Zartman, J., and Hoelzle, D. (2015). Microfluidic device design, fabrication, and testing protocols. Protoc. Exch. DOI 10.1038/protex.2015.069
  • Khan, A., Zhang, S., Vigil, G., Boerckel, J., Howard, S. (2015). Two-Photon Intravital Imaging of a Mouse Brain In Vivo Using Easily Prepared Ruthenium-Poloxamer Nanoprobes in Optics in the Life Sciences, OSA Technical Digest (online) (Optical Society of America, 2015), paper BT1A.3.
  • Yang, L. , Zhang, Y., Guldner, I.H. g, Zhang, S., and Chen, D.Z. (2015). Fast Background Removal in 3D Fluorescence Microscopy Images Using One-Class Learning. In Medical Image Computing and Computer-Assisted Intervention – MICCAI 2015, N. Navab, J. Hornegger, W.M. Wells, and A.F. Frangi, eds. (Springer International Publishing), pp. 292–299.
  • 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: 4.6]
  • 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.