Directional migration of malignant cells toward a gradient of one or more signaling molecules underlies fundamental steps in metastasis, including local invasion of cancer cells, vascular intravasation, and extravasation of cancer cells at secondary sites. Understanding formation of gradients in complex environments with multiple cells and extracellular matrix molecules remains a central challenge in cell migration not only in cancer but also in normal physiology and other diseases. The challenge of understanding gradient formation and cell migration becomes even more difficult in the disordered cellular and extracellular matrix architecture of a tumor. We will meet this challenge through an integrated systems bioengineering approach combining microscale technologies for cell migration, in vitro and in vivo cellular and molecular imaging, and sophisticated multi-scale computational models. This approach will enable us to investigate gradient formation and cell migration in increasingly complex environments, ranging from a 2D system with defined positions of three different cell types to the disorganized structure of a tumor. Using computational modeling to identify key parameters controlling gradient formation and cell migration, we also will experimentally test and validate interventions to block cell migration, which will provide new targets for anti-metastatic therapies. Our research will focus on gradient formation and cell migration controlled by chemokine CXCL12, a signaling molecule that drives metastasis in more than 20 human cancers. CXCL12 exists as six alternatively-spliced isoforms, four of which are expressed in human breast cancers. We recently have shown CXCL12-isoform specific differences in cell migration, resistance to targeted inhibitors, and correlations with disease recurrence and survival in breast cancer. We propose that CXCL12 molecules bound to the extracellular environment drive cell migration, a process referred to as haptotaxis, and differences in binding to the extracellular matrix underlie isoform-specific differences in gradient formation and cell migration. To investigate CXCL12 isoforms in cell migration, we will complete the following specific aims: 1) derive basic cell migration response parameters under simple, defined gradients; 2) using tissue-like geometries, test effects of extracellular matrix composition on migration potency of CXCL12 isoforms; and 3) Quantify in vivo migration in tumor environments with different CXCL12 isoforms. Collectively, this research will advance knowledge of gradient formation in cell migration and point to new treatment strategies for targeting CXCL12 in cancer.

Public Health Relevance

We will combine cutting-edge technologies and methods in engineering, computational modeling, and imaging to understand how gradients of signaling molecules form and control migration of cancer cells, a fundamental process in metastatic cancer. Our studies also will predict and experimentally validate approaches to effectively block cancer cell migration, which we expect will lead to new treatments to prevent and/or eliminate metastases. Since cell migration is essential for normal physiology and multiple other diseases, our experimental approach also establishes an innovative framework for mechanistic studies of cell migration in other contexts.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Zahir, Nastaran Z
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Liu, Chun; Lewin Mejia, Daniela; Chiang, Benjamin et al. (2018) Hybrid collagen alginate hydrogel as a platform for 3D tumor spheroid invasion. Acta Biomater 75:213-225
Buschhaus, Johanna M; Luker, Kathryn E; Luker, Gary D (2018) A Facile, In Vitro 384-Well Plate System to Model Disseminated Tumor Cells in the Bone Marrow Microenvironment. Methods Mol Biol 1686:201-213
Luo, Ming; Shang, Li; Brooks, Michael D et al. (2018) Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling. Cell Metab 28:69-86.e6
Ham, Stephanie Lemmo; Thakuri, Pradip Shahi; Plaster, Madison et al. (2018) Three-dimensional tumor model mimics stromal - breast cancer cells signaling. Oncotarget 9:249-267
Kojima, Taisuke; Takayama, Shuichi (2018) Membraneless Compartmentalization Facilitates Enzymatic Cascade Reactions and Reduces Substrate Inhibition. ACS Appl Mater Interfaces 10:32782-32791
Mertz, David R; Ahmed, Tasdiq; Takayama, Shuichi (2018) Engineering cell heterogeneity into organs-on-a-chip. Lab Chip 18:2378-2395
Cilliers, Cornelius; Menezes, Bruna; Nessler, Ian et al. (2018) Improved Tumor Penetration and Single-Cell Targeting of Antibody-Drug Conjugates Increases Anticancer Efficacy and Host Survival. Cancer Res 78:758-768
Chen, Yu-Chih; Humphries, Brock; Brien, Riley et al. (2018) Functional Isolation of Tumor-Initiating Cells using Microfluidic-Based Migration Identifies Phosphatidylserine Decarboxylase as a Key Regulator. Sci Rep 8:244
Haley, Henry R; Shen, Nathan; Qyli, Tonela et al. (2018) Enhanced Bone Metastases in Skeletally Immature Mice. Tomography 4:84-93
Santos-Vizcaino, Edorta; Haley, Henry; Gonzalez-Pujana, Ainhoa et al. (2018) Monitoring implantable immunoisolation devices with intrinsic fluorescence of genipin. J Biophotonics :e201800170

Showing the most recent 10 out of 16 publications