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AACR Annual Meeting – Ding Li, Danielle D. Hixon, Shannon M. Mumenthaler, Stacey D. Finley

April 10 @ 2:00 pm - 5:00 pm

Session MS.BSB02.01 – Integrative Data Analysis and Systems Modeling

5 – Experimentally-driven mathematical model of tumor angiogenesis mediated by multiple angiogenic factors

Ding Li, Danielle D. Hixon, Shannon M. Mumenthaler, Stacey D. Finley. University of Southern California, Los Angeles, CA
 D. Li: None. D.D. Hixon: None. S.M. Mumenthaler: None. S.D. Finley: None.
Tumor angiogenesis is regulated by multiple pro- and anti-angiogenic factors. Anti-angiogenic drugs target the interconnected network of these angiogenic factors to inhibit neovascularization and tumor growth. However, current anti-angiogenic therapeutics targeting a single angiogenic factor show limited clinical success, prompting the development of combination anti-angiogenic therapy targeting multiple angiogenic factors simultaneously. In cases where anti-angiogenic therapy may be effective, tumors display a wide range of responses, which is not fully understood.
In this work, we use an integrative in vitro imaging and mathematical modeling approach to investigate how tumor angiogenesis is systematically regulated by multiple angiogenic factors and to study the effects of anti-angiogenic therapy. We particularly focus on two pro-angiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), and two anti-angiogenic factors, thrombospondin-1 (TSP1) and platelet factor 4 (PF4). In our in vitro experimental setting human endothelial cells are cultured in a microfluidic organ-on-chip chip platform exposed to angiogenic factors or in the presence of cancer cells to mimic the tumor microenvironment. The cellular responses induced by various concentrations of angiogenic factors are measured through a high content screening (HCS) confocal imaging system to quantify the cell counts, morphological features and vessel characteristics. These data are used to construct a novel mathematical model to capture how the angiogenic factors mediate cross-talk between tumor cells and endothelial cells. By fitting the model to the experimental measurements, we are able to predict the temporal dynamics of cell numbers and concentrations of the angiogenic factors.
Using the model, we generate insights into the effects of angiogenic factors and various anti-angiogenic treatments on tumor cells and endothelial cells. Excitingly, the model can also be applied to investigate how the effect of anti-angiogenic therapy is influenced by inter-tumor heterogeneity. For example, we identified that tumors with lower tumor cell growth rate and higher carrying capacity have a stronger response to anti-VEGF treatment, which indicates that variation in tumor cell growth rates can be a main reason for the observed heterogenous response to anti-VEGF therapy. In addition, we investigate a novel hypothesis regarding synergy between anti-angiogenic and chemotherapeutic agents with the model. Our simulated results suggest a new mechanism in which the chemotherapeutic agent enhances anti-angiogenic therapy simply through reducing the tumor cell growth rate.
Overall, this work generates novel insights into the function of multiple angiogenic factors in tumor angiogenesis, providing a tool that can be further used to test and optimize anticancer therapy.


April 10
2:00 pm - 5:00 pm
Event Category:



Ellison Institute Insights Forum

The Ellison Institute Insights Forum brings together creative and accomplished thinkers to offer their wisdom on some of the key questions we face in fundamentally understanding and controlling cancer and other complex diseases. Through the Ellison Insights Forum conversations, we will brainstorm solutions for some of the thorniest problems in disease biology, particularly cancer, with equally innovative and transformative ideas.

Next Forum: Thursday, March 11 – Role of Evolution in Cancer Treatment

Last Forum Question: How could applying specific principles of evolution/evolutionary theory (and ecology) across biological and temporal scales of cancer revolutionize treatment strategies, reduce resistance, and improve patient outcomes?

Forum Recording: Click HERE to view the discussion between:

Charles Swanton, MD, PhD – senior group leader of the Cancer Evolution and Genome Instability Laboratory at the Francis Crick Institute, and oncologist at the UCL Cancer Institute

Susan Rosenberg, PhD – Ben F Love Chair in Cancer Research; Professor of Molecular & Human Genetics, Biochemistry & Molecular Biology, and Molecular Virology & Microbiology; and Founder and Leader, Mechanisms in Evolution Program, Dan L Duncan Comprehensive Center, Baylor College of Medicine

Robert Gatenby, MD – Department Chair in Radiology and Co-Director Center of Excellence for Evolution Based Therapy at Moffitt Cancer Center

Kenneth Pienta, MD – Donald S. Coffey Professor of Urology and Professor of Oncology, Pharmacology and Molecular Sciences, and Chemical and Biomolecular Engineering at Johns Hopkins University, ACS Professor and Director of Research for the Brady Urological Institute

Moderated by Anna Barker, PhD, Chief Strategy Officer, Ellison Institute and Distinguished Visiting Fellow in Complex Adaptive Systems, Arizona State University and

David B. Agus, MD, Founding Director & CEO, Ellison Institute and Professor of Medicine & Engineering, USC