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.
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.
|Thege, Fredrik I; Lannin, Timothy B; Saha, Trisha N et al. (2014) Microfluidic immunocapture of circulating pancreatic cells using parallel EpCAM and MUC1 capture: characterization, optimization and downstream analysis. Lab Chip 14:1775-84|
|Seigel, Gail M (2014) Review: R28 retinal precursor cells: the first 20 years. Mol Vis 20:301-6|
|Hughes, Andrew D; Marshall, Jocelyn R; Keller, Eric et al. (2014) Differential drug responses of circulating tumor cells within patient blood. Cancer Lett 352:28-35|
|Mitchell, Michael J; King, Michael R (2014) Unnatural killer cells to prevent bloodborne metastasis: inspiration from biology and engineering. Expert Rev Anticancer Ther 14:641-4|
|Rhim, Andrew D; Thege, Fredrik I; Santana, Steven M et al. (2014) Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. Gastroenterology 146:647-51|
|Esch, Mandy B; Smith, Alec S T; Prot, Jean-Matthieu et al. (2014) How multi-organ microdevices can help foster drug development. Adv Drug Deliv Rev 69-70:158-69|
|Chandrasekaran, Siddarth; Marshall, Jocelyn R; Messing, James A et al. (2014) TRAIL-mediated apoptosis in breast cancer cells cultured as 3D spheroids. PLoS One 9:e111487|
|Santana, Steven M; Antonyak, Marc A; Cerione, Richard A et al. (2014) Microfluidic isolation of cancer-cell-derived microvesicles from hetergeneous extracellular shed vesicle populations. Biomed Microdevices 16:869-77|
|Congleton, Johanna; Shen, Miaoqing; MacDonald, Robert et al. (2014) Phosphorylation of c-Cbl and p85 PI3K driven by all-trans retinoic acid and CD38 depends on Lyn kinase activity. Cell Signal 26:1589-97|
|Thadani-Mulero, Maria; Portella, Luigi; Sun, Shihua et al. (2014) Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res 74:2270-82|
Showing the most recent 10 out of 100 publications