Project Title:
Quantitative Shape Description of two dimensional vascular networks

Project Description (short):
Many phenomena, like the cracks that appear in drying clay, produce network-like patterns of branching lines. Our project will create and validate a method for describing the shape of such networks in a quantitative and computer-assisted manner. The networks we study are the two-dimensional vascular networks created by self-organizing human umbilical vein endothelial cells (HUVEC) which are plated in a matrigel well. Digital images of the network are captured digitally with a light microscope, and the shape of the network is analyzed using ImageJ and a plug-in architecture called the Vascular Network Toolkit. Further analysis and quantitative description of the network topology is carried our using Matlab. The goal of the project is to validate the claim that the group's quantitative measurements of a network are sensitive to network robustness. This would show that the tool can be used to help measure the effects of drugs that target cancers that create or co-opt vascular networks. (Longer description here.)

Start Date:
January 2009

End Date:
September or December 2009

Skills needed:

Biology:

We expect a biology student to have completed their STAT 190 and MATH 198 courses, have had a previous research-like experience and/or experience working in a lab. We prefer a student who also has experience with light microscopy. An eagerness to use, learn, and troubleshoot software is a must.

Mathematics:

We expect a mathematics student to have had STAT 290, CS 170 (or CS 180), and MATH 200. Some background with graph theory and ordinary differential equations is a bonus. An eagerness to use, learn, and troubleshoot software is a must.

Students:

2007
Alexandra Wehrman (Mathematics and Computer Science)

2005-2007
Michael Miller (Mathematics and Computer Science)

2004-2005
Kathleen Field (Mathematics)
Chris Miller (Computer Science and Biology)
Jason Hart (Computer Science)

Summer 2004
Kathleen Field (Mathematics)
Chris Miller (Computer Science and Biology)
Laura Hamilton (Computer Science)
Truc Nguyen (Computer Science)
Morgan Reutter (Biology)

Mentors:
Prof. Jason Miller (Mathematics), Prof. Robert Baer (Physiology, ATSU),

About Prof. Miller: Jason earned his B.A. in mathematics at a small private liberal arts school called Saint Olaf College, ventured to North Carolina to get his Ph.D. in mathematics, and headed back north to find real winters. He loves the outdoors (esp. paddling and hiking), music, food, and his Macintosh computers. When he has spare time, he likes to read fiction or essays. He has been at Truman for N years, teaching mathematics and mentoring mathematics, computer science, and biology students in research. He is currently interested in applying his knowledge of the mathematical sciences to answer questions that are important to biologists.

Accomplishments:

• Chris Miller. "An Image Analytic Approach to Characterizing Vasculogenic Networks."
• Truc Phong T. Nguyen. "Image Analysis for Cell Cycle Kinetics." Truman Student Research Conference. April 2005.
• Laura Hamilton. "Image Analysis of Endothelial Networks." Truman Student Research Conference. April 2005.
• Jason Hart. "Image Analytic Skeletonization of Vascular Networks." Truman Student Research Conference. April 2005.
• Kathleen Field. "A Graph Theoretic Approach to Vascular Network Inhibition." Truman Student Research Conference. April 2005.
• Field, Kathleen. "A Graph Theoretic Approach to the Morphometry of Vascular Networks." Mathematics Capstone Paper. May 2005.
• Miller, Michael. "An Open Source Tool to Aid in the Characterization of the Structure of 2D Vascular Networks." Argonne Undergraduate Research Symposium. Argonne National Labs. Fall 2005.
• Jason Miller. "Connectedness As a measure of Robustness." Sigma Xi, Kirksville Chapter. November 17. 2006.
• Miller, Michael. "An Open Source Tool to Aid in the Analysis of 2D Vascular Networks" Undergraduate Poster Session. Joint Mathematics Meeting, New Orleans. January 2007.

Project Description (long):
In cancer, the metabolic support of both the primary tumor and the metastatic cells is generally thought to require the growth of either new blood vessels from existing blood vessels (angiogenesis) or the growth of entirely new blood vessels from precursor cells (vasculogenesis). (2) In addition to providing metabolic support, blood vessels and lymphatic vessels support metastasis, the process by which cells of the primary tumor are transported to distal tissues where they can form satellite tumors (6). There is now evidence that some types of cancer cells (such as melanoma) may "de-differentiate" to the point they, themselves, (rather than precursor cells) may organize into vascular networks by a process called "vasculogenic mimicry." (1, 3, 4)

Clearly, if a pharmaceutical agent can suppress new vascular network growth, one has a powerful adjunct therapy for cancer treatment. To study the biology of these networks, one can grow cells on an artificial extracellular matrix in a tissue culture dish and study phenotypical changes in the networks in the presence of a variety of signal molecules or chemical agents (5). Two examples of these in vitro vascular-like networks are shown above. The vascular or vascular-like networks start as randomly plated individual cells. The cells organize the networks by some combination cell migration, cell shape change, cell adhesion, cell division, and cell death. Being able to model these cell dynamics in a meaningful way is essential if the investigator is to be able to utilize this in vitro system to examine potential therapeutic agents that might either interfere with network formation or expedite network destruction. That is the focus of the current proposal.

References:

1. Folberg R, Hendrix MJ, and Maniotis AJ. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 156: 361-381, 2000.
2. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29: 15-18, 2002.
3. Hendrix MJ, Seftor EA, Hess AR, and Seftor RE. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 3: 411-421, 2003.
4. Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS, and Hendrix MJ. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155: 739-752, 1999.
5. Rybak SM, Sanovich E, Hollingshead MG, Borgel SD, Newton DL, Melillo G, Kong D, Kaur G, and Sausville EA. "Vasocrine" formation of tumor cell-lined vascular spaces: implications for rational design of antiangiogenic therapies. Cancer Res 63: 2812-2819, 2003.
6. Streit M and Detmar M. Angiogenesis, lymphangiogenesis, and melanoma metastasis. Oncogene 22: 3172-3179, 2003.