Research Project 2 focuses on investigating the unique features of populations of tumor cells, both in various regions of primary and metastatic tumor, as well as in the bloodstream.
The First Aim i nvolves extensive specimen sampling of a small number of patients, including various regions of the primary tumor such as the leading invasive edge, the tumor epicenter (among others), as well as tumor cells within afferent and efferent blood vessels of the tumor and tumor cells in blood vessels over time. These population sets of cells will be characterized according to features related to metastability, including overall cytomorphologic structure, surface and cytoplasmic evidence of loss of epithelial-ness, live/dead nuclear features, and E- to N-cadherin switching. The resulting data will provide a tumor topology across the human organism and over time, yielding insight into which populations of tumor cells are important in the process of metastasis.
The Second Aim focuses on the third microenvironment, the bloodstream, which is a transient, yet critical environment for cells undergoing hematogenous metastasis. Investigations are directed at the architecture of tumor cell travel groups in the blood, associ ations between CTCs and other nucleated cells in the bloodstrea m including immunologically active cells, scavenger cells (monocytes), and coating cells (platelets) that may play a critical role in CTC survival/destruction, interactions with non-cellular protein components such as those of the coagulation cascade, and m arkers associated with natural killer cell activity. Methodologies include the incorporation of newly developed techniques to study CTCs in human cancer patient blood samples, utilizing fluorescent immunocytochemistry and standard morphologic stains, combined with sophisticated digital imaging strategies and software applications.
The Third Aim will use the data collected in the first two aims along with clinical patient correlation data to robustly simulate the behaviors of cancer cells as they leave the primary tumor and travel through the blood to metastatic sites.

Public Health Relevance

Certain subsets of cells within a tumor are likely responsible for metastatic disease, which is the cause of death in most cancer patients. Measuring variables to identify various unique populations of tumor cells within a malignancy, and learning how each subset functions during the process of metastasis will allow us to manipulate and ideally prevent such travel, thereby blocking the method by which cancer generally kills.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA143906-05
Application #
8568054
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$302,028
Indirect Cost
$103,957
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Phillips, Kevin G; Kuhn, Peter; McCarty, Owen J T (2014) Physical biology in cancer. 2. The physical biology of circulating tumor cells. Am J Physiol Cell Physiol 306:C80-8
Jones, Casey M; Baker-Groberg, Sandra M; Cianchetti, Flor A et al. (2014) Measurement science in the circulatory system. Cell Mol Bioeng 7:1-14
Dago, Angel E; Stepansky, Asya; Carlsson, Anders et al. (2014) Rapid phenotypic and genomic change in response to therapeutic pressure in prostate cancer inferred by high content analysis of single circulating tumor cells. PLoS One 9:e101777
Phillips, Kevin G; Baker-Groberg, Sandra M; McCarty, Owen J T (2014) Quantitative optical microscopy: measurement of cellular biophysical features with a standard optical microscope. J Vis Exp :
Rodriguez-Lee, Mariam; Kuhn, Peter; Webb, David R (2014) Advancing cancer patient care by integrating circulating tumor cell technology to understand the spatial and temporal dynamics of cancer. Drug Dev Res 75:384-92
Totonchy, Jennifer E; Clepper, Lisa; Phillips, Kevin G et al. (2014) CXCR7 expression disrupts endothelial cell homeostasis and causes ligand-dependent invasion. Cell Adh Migr 8:165-76
Carlsson, Anders; Nair, Viswam S; Luttgen, Madelyn S et al. (2014) Circulating tumor microemboli diagnostics for patients with non-small-cell lung cancer. J Thorac Oncol 9:1111-9
Bethel, Kelly; Luttgen, Madelyn S; Damani, Samir et al. (2014) Fluid phase biopsy for detection and characterization of circulating endothelial cells in myocardial infarction. Phys Biol 11:016002
Bazhenova, Lyudmila; Newton, Paul; Mason, Jeremy et al. (2014) Adrenal metastases in lung cancer: clinical implications of a mathematical model. J Thorac Oncol 9:442-6
Baker-Groberg, Sandra M; Phillips, Kevin G; McCarty, Owen J T (2013) Quantification of volume, mass, and density of thrombus formation using brightfield and differential interference contrast microscopy. J Biomed Opt 18:16014

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