Environmental Regulation of Cancer Stem Cell Plasticity in Metastasis
List of Collaborating Institutions
University of Michigan
Emerging evidence suggests that the physical environment of tumors, including mechanical stress and physico-chemical properties of extracellular matrix, combines with genetics and cell signaling to control plasticity of cancer stem cells during metastasis, the cause of death for > 90% of patients with cancer. Metastasis encompasses processes associated with mesenchymal (invasion) and epithelial (proliferation) phenotypes. Epithelial to mesenchymal (EMT) and mesenchymal to epithelial (MET) transitions define subsets of cancer stem cells, which are implicated as critical drivers of metastasis. In particular, circulating tumor cells (CTCs) and other disseminated tumor cells commonly exhibit both epithelial and mesenchymal features, suggesting that cancer cells transition between these states. Studies of plasticity in cancer stem cells have focused predominantly on primary tumors, in part due to technological challenges of analyzing cell phenotypes and dynamics in other anatomic sites. To overcome these challenges, we will develop engineered environments for three key sites in tumor progression: primary tumor, intravascular compartment, and bone. We hypothesize that extracellular matrix and mechanical properties associated with distinct tumor environments in the metastatic cascade promote EMT and MET transitions of cancer stem cells in triple negative breast cancer. We will systematically interrogate this hypothesis using tunable 3D tissue-engineering technologies pioneered by our group. Specifically, we will develop (i) novel 3D scaffolds and protein matrices to engineer primary and metastatic tumor environments; (ii) microfluidic technologies to model the intravascular compartment; and (iii) new in vivo imaging technologies to measure environmental cues that drive EMT and MET transitions in cancer. Through this physical sciences approach, we will define tumor environments that drive stem cell state transitions in distinct phases of metastasis. EMT and MET transitions occur in almost all solid malignancies, so benefits of this research extend beyond breast cancer and ultimately will lead to better approaches to interrupt metastasis and improve outcomes for patients with multiple types of cancer.
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Dr. Gary Luker, MD, is an Associate Professor of Radiology, Biomedical Engineering, and Microbiology and Immunology at the University of Michigan. His laboratory is part of the University of Michigan Center for Molecular Imaging. The Luker laboratory investigates tumor-stromal signaling pathways that control tumor initiation, metastasis, and tumor dormancy. A key component of this research is development and application of imaging techniques and data processing methods to investigate cell signaling pathways and metabolism. The research encompasses microscale models of cancer environments, mouse models of cancer, and clinical trials. The laboratory also uses computational modeling to identify mechanisms driving metastasis and define potential targets for therapy.
Dr. Joerg Lahann, PhD, is the founding Director of the Biointerfaces Institute at the University of Michigan and Professor of Chemical Engineering, Materials Science and Engineering, and Macromolecular Science and Engineering. The Biointerfaces Institute bridges engineering, physical sciences, and medicine to accomplish cutting-edge basic and translational research. He has been selected by Technology Review as one of the top 100 young scientists and is the recipient of the 2007 Nanoscale Science and Engineering Award, a NSF-CAREER award, and both a single-PI and a team Idea award (2006 & 2011) from the US Department of Defense. In 2011, he was elected as a fellow of the American Institute of Medical and Biological Engineering. His research interests focus at intersections of chemistry, biology, and medicine. The Lahann group has developed a novel technological approach to fabricate anisotropic nano- and microobjects, such as particles or fibers using electrohydrodynamic co-jetting. This approach can generate three-dimensional, hyperporous scaffolds based on multi-compartmental fibers, which can be used to tailor tissue engineered environments to control cell functions such as adhesion and differentiation.
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