Abstract: Despite major strides in understanding of the molecular basis of cancer and cancer therapeutics, the complexities of metastatic process remain poorly understood. Especially in colorectal cancer, it has been severely hampered by limited knowledge about the cells that cause the disease to metastasize through the blood stream. Circulating cells of several lineages are thought to participate in angiogenesis, tumor growth and metastasis. Among these, circulating tumor cells (CTCs) shed from the primary and metastatic carcinomas presumably give rise to blood borne metastases, where as circulating endothelial progenitor cells (CEPCs) from adult bone marrow initiating the pre-metastatic niche. Hence the seed (CTCs) and soil (CEPCs) concept. Although current models explain distinct and important aspects of metastasis, no single model can explain the sum of the cellular changes apparent in human cancer progression and metastasis. I will investigate the inextricable relationship between CTCs, and CEPCs, and their roles in carcinogenesis and metastasis. I propose to take a radical, but integrated technology and biology based translational approach using microfluidic engineering tools to identify, and study the biological relevance of these rare cells in peripheral blood. This approach will seek the following (1) Does the levels of CEPCs and CTCs in early and late stages of colon cancer correlate with each other along with tumor volume and clinical course (2) Can dynamic changes in their load during the course of treatment plan can predict the clinical outcome of the therapy (3) Are there any changes to phenotypic and biological characteristics of these cells that distinguish prognostic subtypes (4) What is the effect of CEPCs on CTCs when cocultured and the fundamental biology of interaction (5) Can we expand these cells in vitro to identify the true """"""""metastatic precursors"""""""" or """"""""cancer stem cells"""""""" and to determine biomarkers of angiogenesis and metastasis as potential therapeutic targets. Public Health Relevance: There may not be a direct medical benefit to individual participants. However, through this research program, I expect to learn more about novel metastatic markers. Using a novel integrated microfluidic technology, the biological significance of circulating cells in carcinogenesis and metastasis will be investigated. The risks of participating in the research project are reasonable to assume in order to possibly improve diagnostic, prognostic and treatment capabilities for the participants and future patients with cancer.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
7DP2OD006672-02
Application #
8250226
Study Section
Special Emphasis Panel (ZGM1-NDIA-O (02))
Program Officer
Basavappa, Ravi
Project Start
2009-09-30
Project End
2014-06-30
Budget Start
2010-09-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$1,930,771
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Zhuo; Shiratsuchi, Hiroe; Palanisamy, Nallasivam et al. (2017) Expanded Circulating Tumor Cells from a Patient with ALK-Positive Lung Cancer Present with EML4-ALK Rearrangement Along with Resistance Mutation and Enable Drug Sensitivity Testing: A Case Study. J Thorac Oncol 12:397-402
Murlidhar, Vasudha; Reddy, Rishindra M; Fouladdel, Shamileh et al. (2017) Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers. Cancer Res 77:5194-5206
Nagrath, Sunitha; Jack, Rhonda M; Sahai, Vaibhav et al. (2016) Opportunities and Challenges for Pancreatic Circulating Tumor Cells. Gastroenterology 151:412-26
Kozminsky, Molly; Wang, Yang; Nagrath, Sunitha (2016) The incorporation of microfluidics into circulating tumor cell isolation for clinical applications. Curr Opin Chem Eng 11:59-66
Reddy, Rishindra M; Murlidhar, Vasudha; Zhao, Lili et al. (2016) Pulmonary venous blood sampling significantly increases the yield of circulating tumor cells in early-stage lung cancer. J Thorac Cardiovasc Surg 151:852-858
Yoon, Hyeun Joong; Shanker, Apoorv; Wang, Yang et al. (2016) Tunable Thermal-Sensitive Polymer-Graphene Oxide Composite for Efficient Capture and Release of Viable Circulating Tumor Cells. Adv Mater 28:4891-7
Murlidhar, Vasudha; Zeinali, Mina; Grabauskiene, Svetlana et al. (2014) A radial flow microfluidic device for ultra-high-throughput affinity-based isolation of circulating tumor cells. Small 10:4895-904
Kanwar, Shailender Singh; Dunlay, Christopher James; Simeone, Diane M et al. (2014) Microfluidic device (ExoChip) for on-chip isolation, quantification and characterization of circulating exosomes. Lab Chip 14:1891-900
Yoon, Hyeun Joong; Kozminsky, Molly; Nagrath, Sunitha (2014) Emerging role of nanomaterials in circulating tumor cell isolation and analysis. ACS Nano 8:1995-2017
Zhang, Zhuo; Nagrath, Sunitha (2013) Microfluidics and cancer: are we there yet? Biomed Microdevices 15:595-609

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