The adhesion to the vessel wall and extravasation of circulating tumor cells (CTC) is a complex interplay between hydrodynamic shear forces and chemical receptor-ligand binding kinetics, and is critical to the hematologic spread of many metastatic cancers including those originating from prostate, breast, colon, and skin. Consistent with the overarching organizational framework of this proposed Center, Project 3 will deconvolve the complexity of metastatic cell adhesion in the bloodstream by utilizing experimental and theoretical approaches derived from the physical sciences. A major question that we will address is: Can CTC adhesion to the vessel wall and extravasation be understood as a multistep cascade, similar to leukocyte recruitment in inflammation? The proposed research is organized around three specific aims.
Aim 1 : Application of a multiscale model to predict rolling and firm adhesion of circulating tumor cells. The multiparticle adhesive dynamics simulation with stochastic selectin:carbohydrate and MUC1:ICAM-1 binding will be used with input parameters obtained from primary tumor cells isolated from the blood of metastatic cancer patients.
Aim 2 : Characterization of the adhesion of CTCs to defined molecular surfaces and endothelial cell monolayers under physiological shear stress. Cancer cells spiked into whole blood will be perfused through microfluidic flow chambers to test adhesion predictions of Aim 1 and identify differences between microvascular endothelial cells from different tissues.
Aim 3 : Study of CTC adhesion, mechanical plugging and extravasation in a live animal model. Fluorescently labeled cancer cells will be observed in the microvessels of mouse brain and skull using multiphoton intravital microscopy, to determine the relative importance of adhesion receptors and mechanical plugging in tumor cell recruitment from the bloodstream. Taken together, the proposed research will lead to new pathways to intervene in the development of cancer, such as the quantitative evaluation of biomolecular targets for. disrupting metastatic cell adhesion.

Public Health Relevance

This PS-OC brings together expert teams from the fields of physics, nano and microfabrication, engineering and cancer biology to develop novel trans-disciplinary approaches to better understand the complexity of cancer metastasis, the aspect of cancer that directly leads to patient morbidity and mortality. Approaches developed by physical scientists will be focused on the study of cancer. Our studies aim to identify novel mechanisms used by cancer cells, but not normal cells, for growth and metastasis to distant body sites. These new mechanism provide novel drug targets, that aim towards arresting cancer metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-SRLB-9)
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Cornell University
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Cao, Xuan; Moeendarbary, Emad; Isermann, Philipp et al. (2016) A Chemomechanical Model for Nuclear Morphology and Stresses during Cell Transendothelial Migration. Biophys J 111:1541-1552
McCoy, Michael G; Seo, Bo Ri; Choi, Siyoung et al. (2016) Collagen I hydrogel microstructure and composition conjointly regulate vascular network formation. Acta Biomater 44:200-8
Denais, Celine M; Gilbert, Rachel M; Isermann, Philipp et al. (2016) Nuclear envelope rupture and repair during cancer cell migration. Science 352:353-8
Duncan, Sara M; Seigel, Gail M (2016) High-contrast enzymatic immunohistochemistry of pigmented tissues. J Biol Methods 3:
Seigel, G M; Sharma, S; Hackam, A S et al. (2016) HER2/ERBB2 immunoreactivity in human retinoblastoma. Tumour Biol 37:6135-42
Chandrasekaran, Siddarth; Chan, Maxine F; Li, Jiahe et al. (2016) Super natural killer cells that target metastases in the tumor draining lymph nodes. Biomaterials 77:66-76
Wang, Suming; Blois, Anna; El Rayes, Tina et al. (2016) Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. Sci Transl Med 8:329ra34
Hall, Matthew S; Alisafaei, Farid; Ban, Ehsan et al. (2016) Fibrous nonlinear elasticity enables positive mechanical feedback between cells and ECMs. Proc Natl Acad Sci U S A 113:14043-14048
Bordeleau, Francois; Chan, Bryan; Antonyak, Marc A et al. (2016) Microvesicles released from tumor cells disrupt epithelial cell morphology and contractility. J Biomech 49:1272-9
Levin, Michael; Klar, Amar J S; Ramsdell, Ann F (2016) Introduction to provocative questions in left-right asymmetry. Philos Trans R Soc Lond B Biol Sci 371:

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