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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA143876-04
Application #
8379970
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$325,353
Indirect Cost
Name
Cornell University
Department
Type
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Carey, Shawn P; Martin, Karen E; Reinhart-King, Cynthia A (2017) Three-dimensional collagen matrix induces a mechanosensitive invasive epithelial phenotype. Sci Rep 7:42088
Song, Young Hye; Warncke, Christine; Choi, Sung Jin et al. (2017) Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells. Matrix Biol 60-61:190-205
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
Davison, Angus; McDowell, Gary S; Holden, Jennifer M et al. (2016) Formin Is Associated with Left-Right Asymmetry in the Pond Snail and the Frog. Curr Biol 26:654-60
Duncan, Sara M; Seigel, Gail M (2016) High-contrast enzymatic immunohistochemistry of pigmented tissues. J Biol Methods 3:
Wayne, Elizabeth C; Chandrasekaran, Siddarth; Mitchell, Michael J et al. (2016) TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer. J Control Release 223:215-223
Carey, Shawn P; Goldblatt, Zachary E; Martin, Karen E et al. (2016) Local extracellular matrix alignment directs cellular protrusion dynamics and migration through Rac1 and FAK. Integr Biol (Camb) 8:821-35
McDowell, G S; Philpott, A (2016) New Insights Into the Role of Ubiquitylation of Proteins. Int Rev Cell Mol Biol 325:35-88
Li, Jiahe; Sharkey, Charles C; Wun, Brittany et al. (2016) Genetic engineering of platelets to neutralize circulating tumor cells. J Control Release 228:38-47
Dimonte, Alice; Adamatzky, Andrew; Erokhin, Victor et al. (2016) On chirality of slime mould. Biosystems 140:23-7

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