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3D Biomimetic Model for Cellular Invasion in Angiogenesis and Cancer

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3D Biomimetic Model for Cellular Invasion in Angiogenesis and Cancer University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 3d Biomimetic Model for Cellular Invasion in Angiogenesis and Cancer Duc-Huy Nguyen University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biomedical Commons, and the Chemical Engineering Commons Recommended Citation Nguyen, Duc-Huy, "3d Biomimetic Model for Cellular Invasion in Angiogenesis and Cancer" (2016). Publicly Accessible Penn Dissertations. 1915. https://repository.upenn.edu/edissertations/1915 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1915 For more information, please contact [email protected]. 3d Biomimetic Model for Cellular Invasion in Angiogenesis and Cancer Abstract Cell migration is an essential and highly regulated process. Cells migrate to vascularize tissues, to form tissue, and to respond to inflammation. Unfortunately, cell migration is also involved in numerous pathological conditions such as in invasive tumors. Cells can migrate as individual cells or as collective groups of cells. Particularly important in cell migration is the collective migration of cells as it is a hallmark of tissue remodeling events during embryonic morphogenesis, wound repair, and cancer invasion. Perhaps, angiogenesis is one of the most crucial collective migration processes as it is involved in multiple physiological and pathological conditions such as formation of vasculature, wound healing, cancer progression and metastasis. During angiogenesis, endothelial cells migrate collectively from existing vasculature in response to a complex biochemical and mechanical cues to form multicellular structures that eventually develop into new functional blood vessels. Angiogenesis is also a highly dynamic process where multiple cells rearrange and coordinate within a sprout. Such dynamic rearrangement requires different cytoskeletal regulators such as Rho GTPases proteins (RhoA, Rac, and Cdc42). Although the roles of Rho GTPase proteins have been well characterized in 2D cell migration, little is known about their contributions in angiogenic morphogenesis. Here, we engineered a 3D biomimetic microfluidic-based device, called AngioChip, where endothelial cells are induced to migrate collectively from a pre-formed biomimetic cylindrical blood vessel into a 3D interstitial collagen matrix. The sprouts in our AngioChip demonstrate in vivo-like morphogenetic features such as formation of tip-stalk cells, lumen formation, filopodial-like protrusions in leading tip cells, and formation of perfusable neovessels. Using this system, we examine the roles of Cdc42 to regulate many aspects of angiogenic morphogenesis. We find that disturbing Cdc42 activity reduces formation of branches, migration speed, and collective migration. Additionally, Cdc42 also negatively regulate filopodia formation. eW also develop the AngioChip into a pancreatic ductal adenocarcinoma (PDAC) on a chip to investigate the interactions between pancreatic cancer cells and blood vessels. Vascular invasion, where PDAC cells invaded towards the vasculature during tumor progression, is a hallmark of metastatic PDAC. Nevertheless, how pancreatic tumor cells interact with the blood vessels remains largely unknown. Using our PDAC-on-a- chip, we reveal a striking observation where PDAC cells invade and de-endothelialize the blood vessels. This de-endothelialization process leads to vascular replacement in the blood vessels and is mediated by proliferation of PDAC through Nodal/Activin-ALK7 signaling. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Chemical and Biomolecular Engineering First Advisor Christopher S. Chen Keywords angiogenesis, biomimetic, cancer, Cdc42, microfluidic, pancreatic Subject Categories Biomedical | Chemical Engineering This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/1915 3D BIOMIMETIC MODEL FOR CELLULAR INVASION IN ANGIOGENESIS AND CANCER Duc-Huy Tran Nguyen A DISSERTATION In Chemical and Biomolecular Engineering Presented to the Faculties of the University of Pennsylvania In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2016 Supervisor of Dissertation Signature: ______________________________ Christopher S. Chen, M.D., Ph.D., Adjunct Professor of Bioengineering and Chemical and Biomolecular Engineering; Professor of Biomedical Engineering, Boston University; Wyss Institute for Biologically Inspired Engineering at Harvard University Graduate Group Chairperson Signature: ______________________________ John C. Crocker, Ph.D., Professor of Chemical and Biomolecular Engineering. Dissertation Committee: Christopher S. Chen, M.D., Ph.D., Adjunct Professor of Bioengineering and Chemical and Biomolecular Engineering; Professor of Biomedical Engineering, Boston University; Wyss Institute for Biologically Inspired Engineering at Harvard University Kathleen J. Stebe, Ph.D., Richer and Elizabeth Goodwin Professor, Department of Chemical and Biomolecular Engineering, University of Pennsylvania Scott L. Diamond, Ph.D., Arthur E. Humphrey Professor, Department of Chemical and Biomolecular Engineering, University of Pennsylvania Sandra W. Ryeom, Ph.D., Assistant Professor, Department of Cancer Biology, University of Pennsylvania 3D BIOMIMETIC MODEL FOR CELLULAR INVASION IN ANGIOGENESIS AND CANCER COPYRIGHT 2016 Duc–Huy Tran Nguyen This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit http://creativecommons.org/licenses/by-ny-sa/2.0/ ACKNOWLEDMENTS Thank you to the following people: Family To my parents, Minh-Lien Tran and Duc Van Nguyen: As I am writing my dissertation, I remember you said this to me many times when I was young: “We don’t have money for you to inherit, so we hope to leave you with a great education, and we hope you continue to learn and thrive to succeed in life”. This was the reason you both had given up a comfortable life in Vietnam to allow me a chance to arrive in the US, the land of opportunities to acquire a better education and a better life. I also remember vividly that you both full-heartedly supported me when I was a young kid learning about science. Dad, whenever I asked, without any hesitation, you drove me to bookstores, and despite me spending hours reading chemistry, physics, and math books, you patiently waited outside. This was how I discovered my passion for science. Mom, you have always supported me fully as I explored my different interests from learning how to play an electronic keyboard to practicing Aikido. I know how hard it is that you let your only child live across the country, whom you only get to see once or twice a year. I am deeply grateful for all your moral supports and the sacrifices to let me follow my dreams and passions. To my aunt, Loc Tran: I admire you for being such a generous, caring and loving individual. It is very inspiring to be around you. Thank you very much for being our rock of supports as we first stepped our first few footsteps into the land of opportunities. And thank you very much for always being there for my parents and me all these years. To all my extended family members in Vietnam and in the US: thank you for your support and always believing in me. To Andrew Menning: Sometimes, my labmates ask why I am often optimistic and positive about science despite how much frustrating sometimes science can be. I have no one else but you to be thankful for. You have always listened and cheered me up when my experiments failed. Thanks for iii your patience, kindness, and words of wisdom and through those, I have discovered many things about myself. It has been an amazing 3+ years of adventure with you and many more years to come. Thank you very much for always being there and believing in me. Scientific Mentors Dr. Christopher Chen: Thank you very much for creating a very open and collaborative scientific environment. I cannot thank you enough for being an extremely supportive and encouraging advisor. Your words of wisdom, your mentorship and career advice are invaluable. Looking back on all of these years, I will always be proud to say that I made the right decision to join and do great science in your lab. Thanks for setting up a great model of what it is to be a great leader in a scientific community. Dr. Sandra Ryeom: I am very thankful for your mentorship and guidance. Thank you for your invaluable inputs as we were writing our AngioChip paper, and especially your valuable career advice as I started to apply for postdoctoral positions. Dr. Kathleen Stebe and Dr. Scott Diamond: thank you very much for your guidance and support of my work, and your valuable scientific inputs whether it is during my thesis committee meetings or at the CBE department’s social happy hours. Members of Chenlab I have had a privileged opportunity to be surrounded by many wonderful minds and smart people in Chenlab. Not only you inspired me to think outside of the box, but you also set up an example of hard work and dedication. You are not only my colleagues but also my true friends over the years: Styliani Alimperti, Brendon Baker, Jan Baranski, Evangelia Bellas, Brandon Blakely, Thomas Boudou, Mark Breckenridge, Ritika Chaturvedi, Daniel Cheng, Colin Choi, Anant Chopra, Daniel Cohen, Ravi Desai, Jeroen Eyckmans, Peter Galie, Lin Gao, Elaine Jenson, Laurie Kelleher, Matt Kutys, Esak Lee, Wesley Legant, Jennifer
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