Biomolecular Recognition of Receptor Proteins and Their Roles in Tumor Cell Adhesion in the Vasculature

Cell-cell adhesive interactions play a pivotal role in major pathophysiological vascular processes, such as inflammation, thrombosis, and cancer metastasis, and are regulated by hemodynamic forces generated by blood flow. Elucidating molecular and biophysical properties of membrane receptor-ligand interactions may provide guidelines for developing promising therapeutic strategies to combat these fatal diseases. Membrane receptor-ligand interaction is not a simple lock-and-key problem in which only the right key can operate the lock. The protein-protein interface is constructed by a series of amino acid residues; therefore, the binding free energy may not be uniformly distributed among these interfacial residues. The goal of my research career is to elucidate the biomolecular recognition of receptor proteins and their roles in tumor cell adhesion in the vasculature.

My research expertise is in the area of microfluidics and protein-ligand interactions. I received Ph.D. at the University of Arizona, where my dissertation focuses on the effect of shear flow on the attachment, deformation and detachment of tumor cells in microchannels. In addition to research training, I also had a precious opportunity to participate in the development of a new laboratory. At the Johns Hopkins University, I continue my research with Prof. Konstantinos Konstantopoulos to investigate the complex interplay and structure-activity relationship of receptor-ligand interactions pertinent to inflammation and cancer metastasis. In 2011, I received a postdoctoral fellowship award from the American Heart Association.

There are three core topics in my research as follows: (1) Lab-on-a-chip devices: Design and fabricate microfluidic devices for studying the cell adhesion in pathophysiological vascular processes, such as inflammation and cancer metastasis. (2) Bio-molecular recognition: Quantify the kinetic and micromechanical properties (such as dissociation rate, reactive compliance and tensile strength) of membrane protein-ligand interactions under dynamic loading. (3) Tumor cell mechanics: Develop models and experimental techniques to study the effect of shear flow on the cell deformation and migration during intra- and extra-vasation processes. Cumulatively, these studies will provide scientific insights on how the tumor cell receptors interact with their target molecules in the vasculature.

Selected peer-reviewed publications:

1.  Z. Tong*, L.S.L. Cheung*, K.J. Stebe and K. Konstantopoulos, "Selectin-mediated Adhesion in Shear Flow Using Micropatterned Substrates: Multiple-Bond Interactions Govern the Critical Length for Cell Binding", Integr Biol, 2012 (accepted). *Equally contribution authors

2.  L.S.L. Cheung, M. Kanwar, M. Ostermeier and K. Konstantopoulos, "A Hot-Spot Motif Characterizes the Interface Between a Designed Ankyrin-Repeat Protein and Its Target ligand". Biophys J, 102(3), 407-416, 2012.

3.  X.J. Zheng, L.S.L. Cheung, J.A. Schroeder, L. Jiang and Y. Zohar, "Cell Receptor and Surface Ligand Density Effects on Dynamic States of Adhering Circulating Tumor Cells", Lab Chip, 11(20), 3431-3439, 2011.

4.  X. Zheng, L.S.L. Cheung, J.A. Schroeder, L. Jiang and Y. Zohar, "A High-Performance Microsystem for Isolating Circulating Tumor Cells", Lab Chip, 11(19), 3269-3276, 2011.

5.  L.S.L. Cheung, X. Zheng, L. Wang, J.C. Baygents, R. Guzman, J.A. Schroeder, R.L. Heimark and Y. Zohar, "Adhesion Dynamics of Circulating Tumor Cells under Shear Flow in a Bio-Functionalized Microchannel", J Micromech Microeng, 21(5), 054033, 2011.

6.  P. Sundd, M.K. Pospieszalska, L.S.L. Cheung, K. Konstantopoulos and K. Ley, "Biomechanics of Leukocyte Rolling", Biorheology, 48, 1-35, 2011.

7.  L.S.L. Cheung, K. Konstantopoulos, "An Analytical Model for Determining Two-Dimensional Receptor-Ligand Kinetics", Biophys J, 100(10), 2338-2346, 2011.

8.  L.S.L. Cheung, P.S. Raman, E.M. Balzer, D. Wirtz and K. Konstantopoulos, "Biophysics of Selectin–Ligand Interactions in Inflammation and Cancer", Phys Biol, 8(1), 015013, 2011.

9.  T. Gudipaty, M. T. Stamm, L.S.L. Cheung, L. Jiang and Y. Zohar, "Cluster Formation and Growth in Microchannel Flow of Dilute Particle Suspension", Microfluid Nanofluid, 10(3), 661-669, 2010.

10.  L.S.L. Cheung, X. Zheng, L. Wang, R. Guzman, J.A. Schroeder, R.L. Heimark, J.C. Baygents and Y. Zohar, “Kinematics of Specifically Captured Circulating Tumor Cells in Bio-Functionalized Microchannels”, J Microelectromech S, 19(4), 752-763, 2010.

11.  L.S.L. Cheung, X. Zheng, A. Stopa, J.C. Baygents, R. Guzman, J.A. Schroeder, R.L. Heimark and Y. Zohar, “Detachment of Captured Cancer Cells under Flow Acceleration in a Bio-functionalized Microchannel”, Lab Chip, 9, 1721-1731, 2009.

12.  M. Lee, L.S.L. Cheung, Y.K. Lee and Y. Zohar, “Height Effect on Nucleation-Site Activity and Size-Dependent Bubble Dynamics in Microchannel Convective Boiling", J Micromech Microeng, 15, 2121-2129, 2005.

Book chapters:

13.  L.S.L. Cheung, P.S. Raman, D. Wirtz and K. Konstantopoulos, "Biophysics of Selectin-Mediated Cell Adhesion", Comprehensive Biophysics: Cell Biophysics, Elsevier, 7, 2012 (in press May 31st).

14.  L.M. Lee, L.S.L. Cheung and Y. Zohar, “Microfluidics: Device Science and Technology”, CISM Courses and Lectures, International Centre for Mechanical Sciences, Springer, 428, 157-211, 2006.