Computational tools have become increasingly important in enabling progress in biomedical research. The objective of this proposal is to apply emerging technologies in developing multi-scale computational approaches for studying heterotypic cell-cell collision and adhesion in the near wall region under dynamic shear forces. In particular, we focus on leukocyte (PMN)-melanoma cell emboli formation in a non-linear shear flow and subsequent tethering to the vascular endothelium (EC) as a result of cell-cell aggregation. The extent of tumor cell adhesion to a vessel wall is governed by the kinetic formation/disruption of receptor- ligand bonds, the hydrodynamic shear environment and the heterotypic cell populations within the circulation. Preliminary studies found PMNs increased melanoma cell extravasation, which involves PMNs initially tethering on the EC and subsequently capturing melanoma cells and maintaining them in close proximity to the EC. Results have indicated a novel finding and led to an important hypothesis that PMN-facilitated melanoma cell arrest on the EC is mediated by intercellular adhesion molecule-1 (ICAM-1)/beta2-integrin binding and is influenced by hydrodynamic shear rates and heterotypic cell populations. The rationale for this research is to generate computational tools using innovative multi-scale computational fluid dynamics (CFD) and population balance (PB) modeling to study the heterotypic cell-cell interactions that facilitate tumor cell adhesion to the EC and subsequent extravasation.
Specific aims are: 1) develop a PB model to simulate the shear-induced collision/aggregation of melanoma cells to PMNs near the EC in a statistical manner;2) develop a 3-D CFD simulation to assess the role of PMN-melanoma cell interaction in melanoma arrest on the EC;3) validate the models by using in vitro flow experiments and use the models to expand the current knowledge of the molecular mechanisms of tumor cell adhesion under flow conditions. This study will yield new evidence for the complex role of hemodynamics, heterotypic cell populations, and PMN-melanoma adhesion in the recruitment of metastatic cancer cells to the EC in the microcirculation during metastasis, which will be significant in fostering new cross-disciplinary approaches to cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125707-04
Application #
7803609
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Couch, Jennifer A
Project Start
2007-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$234,485
Indirect Cost
Name
Pennsylvania State University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Zhang, Pu; Feng, Shan; Liu, Gentao et al. (2016) CD82 suppresses CD44 alternative splicing-dependent melanoma metastasis by mediating U2AF2 ubiquitination and degradation. Oncogene 35:5056-5069
Zhang, Pu; Feng, Shan; Liu, Gentao et al. (2016) Mutant B-Raf(V600E) Promotes Melanoma Paracellular Transmigration by Inducing Thrombin-mediated Endothelial Junction Breakdown. J Biol Chem 291:2087-106
Zhang, Pu; Fu, Changliang; Hu, Yijuan et al. (2015) C6-ceramide nanoliposome suppresses tumor metastasis by eliciting PI3K and PKC? tumor-suppressive activities and regulating integrin affinity modulation. Sci Rep 5:9275
Haakenson, Jeremy K; Khokhlatchev, Andrei V; Choi, Younhee J et al. (2015) Lysosomal degradation of CD44 mediates ceramide nanoliposome-induced anoikis and diminished extravasation in metastatic carcinoma cells. J Biol Chem 290:8632-43
Khanna, P; Chung, C-Y; Neves, R I et al. (2014) CD82/KAI expression prevents IL-8-mediated endothelial gap formation in late-stage melanomas. Oncogene 33:2898-908
Weidert, Eric; Pohler, Steven E; Gomez, Esther W et al. (2014) Actinomyosin contraction, phosphorylation of VE-cadherin, and actin remodeling enable melanoma-induced endothelial cell-cell junction disassembly. PLoS One 9:e108092
Zhang, Pu; Goodrich, Chris; Fu, Changliang et al. (2014) Melanoma upregulates ICAM-1 expression on endothelial cells through engagement of tumor CD44 with endothelial E-selectin and activation of a PKC?-p38-SP-1 pathway. FASEB J 28:4591-609
Ribeiro, Alexandre J S; Khanna, Payal; Sukumar, Aishwarya et al. (2014) Nuclear stiffening inhibits migration of invasive melanoma cells. Cell Mol Bioeng 7:544-551
Ozdemir, Tugba; Zhang, Pu; Fu, Changliang et al. (2012) Fibrin serves as a divalent ligand that regulates neutrophil-mediated melanoma cells adhesion to endothelium under shear conditions. Am J Physiol Cell Physiol 302:C1189-201
Fu, Yi; Kunz, Robert; Wu, Jianhua et al. (2012) Study of local hydrodynamic environment in cell-substrate adhesion using side-view ?PIV technology. PLoS One 7:e30721

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