Multiscale modeling of leukocyte-tumor cell adhesion to endothelium in shear flow

Project: Research project

Description

DESCRIPTION (provided by applicant): 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.
StatusFinished
Effective start/end date7/1/075/31/12

Funding

  • National Institutes of Health: $234,485.00
  • National Institutes of Health: $232,354.00
  • National Institutes of Health: $235,598.00
  • National Institutes of Health: $230,950.00

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Cell adhesion
Shear flow
Tumors
Cells
Adhesion
Computational fluid dynamics
Agglomeration
Hydrodynamics
Microcirculation
Oncology
Hemodynamics
Shear deformation
Ligands
Molecules
Kinetics
Computer simulation
Experiments