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Extracellular Matrix Regulates Fibroblast Heterogeneity and Tumorigenesis

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Extracellular Matrix Regulates Fibroblast Heterogeneity and Tumorigenesis University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Extracellular Matrix Regulates Fibroblast Heterogeneity And Tumorigenesis Diana Leigh Avery University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Cell Biology Commons, Oncology Commons, and the Pharmacology Commons Recommended Citation Avery, Diana Leigh, "Extracellular Matrix Regulates Fibroblast Heterogeneity And Tumorigenesis" (2017). Publicly Accessible Penn Dissertations. 2173. https://repository.upenn.edu/edissertations/2173 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2173 For more information, please contact [email protected]. Extracellular Matrix Regulates Fibroblast Heterogeneity And Tumorigenesis Abstract Heterogeneous activated fibroblasts that deposit and remodel extracellular matrix (ECM) comprise desmoplasia, a key regulator of tumor development. The divergent outcomes in response to varied therapies targeting intratumoral desmoplasia underscore the pressing need to delineate the intricate role of a heterogeneous stroma in tumorigenesis. Fibroblast activation protein (FAP) and alpha-smooth muscle actin (αSMA) identify distinct, yet overlapping, activated fibroblast subsets in myriad tumor types, fibrosis, and wound healing. FAPHi reactive fibroblasts and αSMAHi myofibroblasts can exert divergent influences on tumor progression. However, the factors that drive this phenotypic heterogeneity and the unique functional roles of these distinct phenotypes are not yet understood. By comparing fibroblast activation on fibronectin- and collagen I-coated hydrogels of varying stiffness, I demonstrated that a convergence of ECM composition, elasticity, and TGF-β signaling governs activated fibroblast phenotypic heterogeneity. Furthermore, by characterizing gene expression signatures, I revealed potentially unique roles of activated fibroblast subsets in tissue remodeling. In addition to its utility as a marker of activated fibroblasts, FAP also constitutes a highly attractive drug target due to its selective expression in the tumor microenvironment and its pro-tumorigenic proteolytic activity. FAP-mediated proteolysis of collagen I and III fragments promotes collagen clearance. However, the potential mechanistic link between FAP’s role in collagen proteolysis and tumorigenesis is not yet known. I investigated the role of FAP-dependent collagen proteolysis and ECM remodeling in tumorigenesis using both a spontaneous oncogenic Kras-driven lung tumor model and fibroblast-derived matrices. I found that Fap genetic deletion promotes intratumoral fibrillar collagen accumulation and attenuates lung tumor multiplicity, size, progression, and proliferation. Furthermore, I obtained preliminary evidence that Fap-/- lung fibroblasts produce ECM with enhanced fibrillar collagen accumulation, which directly impedes both tumor cell proliferation and motility. Taken together, my research underscores the essential role of ECM remodeling in regulating key aspects of tumorigenesis, such as intratumoral fibroblast heterogeneity, proliferation, and invasion. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Pharmacology First Advisor Ellen Pur� Keywords Biomechanics, Desmoplasia, Extracellular Matrix, Fibroblast, Tumor Microenvironment Subject Categories Cell Biology | Oncology | Pharmacology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2173 EXTRACELLULAR MATRIX REGULATES FIBROBLAST HETEROGENEITY AND TUMORIGENESIS Diana Avery A DISSERTATION in Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2017 Supervisor of Dissertation _____________________ Ellen Puré, Ph.D. Professor of Biomedical Sciences Graduate Group Chairperson _____________________ Julie Blendy, Ph.D. Professor of Pharmacology Dissertation Committee Rebecca G. Wells, M.D., Associate Professor of Medicine Richard K. Assoian, Ph.D., Professor of Pharmacology Sandra W. Ryeom, Ph.D., Associate Professor of Cancer Biology Edna Cukierman, Ph.D., Associate Professor of Cancer Biology, Fox Chase Cancer Center DEDICATION To my family for their love and support ii ACKNOWLEDGMENT I would first like to thank my advisor, Ellen Puré, for her support and guidance over the past few years, which helped me develop as both a scientist and scholar. I would like to thank members of the Puré lab (past and present): Priya Govindaraju, Rachel Blomberg, Mia Krolikoski, Leslie Hopper, James Monslow, Allyson Lieberman, Albert Lo, Michael Leibowitz, Toru Kimura, John Chojnowski, Lisa Chang, Irene Crichton, Michele Jacob, Sonali Majumdar, and Ming-Hui Fan, for stimulating scientific discussion and for making the past few years so enjoyable. I would like to thank Paola Castagnino of the Biomechanics Core Facility of the Institute for Translational Medicine and Therapeutics (ITMAT) for providing hydrogels and technical support. I would also like to thank Colleen McEntee and Sarah Rauers as well as our collaborators, Susan Volk, Becky Brisson, and Chelsea Burgwin, for all their assistance. I would like to acknowledge my thesis committee: Rebecca Wells (Chair), Richard Assoian, Sandra Ryeom, and Edna Cukierman, for their expertise and insight. I want to thank my family and friends for their support and advice. I especially want to thank my parents, sisters, brothers-in-law, niece, and nephew for their support and love. I also want to thank my classmates of the Pharmacology Graduate Group: Sima Patel, Abby Christian, Mansi Shinde, Bridgin Lee, Jackie St. Louis, Kevin Patel, Mike Chiorazzo, Natalie Daurio, Nishita Shastri, John O’Donnell, and Brian Weiser. You all made my time in graduate school more enjoyable by providing friendship and support. Finally, I would like to thank the Pharmacology Graduate Group, especially Sarah Squire and Julie Blendy, for this experience. iii ABSTRACT EXTRACELLULAR MATRIX REGULATES FIBROBLAST HETEROGENEITY AND TUMORIGENESIS Diana Avery Ellen Puré Heterogeneous activated fibroblasts that deposit and remodel extracellular matrix (ECM) comprise desmoplasia, a key regulator of tumor development. The divergent outcomes in response to varied therapies targeting intratumoral desmoplasia underscore the pressing need to delineate the intricate role of a heterogeneous stroma in tumorigenesis. Fibroblast activation protein (FAP) and alpha-smooth muscle actin (αSMA) identify distinct, yet overlapping, activated fibroblast subsets in myriad tumor types, fibrosis, and wound healing. FAPHi reactive fibroblasts and αSMAHi myofibroblasts can exert divergent influences on tumor progression. However, the factors that drive this phenotypic heterogeneity and the unique functional roles of these distinct phenotypes are not yet understood. By comparing fibroblast activation on fibronectin- and collagen I- coated hydrogels of varying stiffness, I demonstrated that a convergence of ECM composition, elasticity, and TGF-β signaling governs activated fibroblast phenotypic heterogeneity. Furthermore, by characterizing gene expression signatures, I revealed potentially unique roles of activated fibroblast subsets in tissue remodeling. In addition to its utility as a marker of activated fibroblasts, FAP also constitutes a highly attractive drug target due to its selective expression in the tumor microenvironment and its pro-tumorigenic proteolytic activity. FAP-mediated proteolysis iv of collagen I and III fragments promotes collagen clearance. However, the potential mechanistic link between FAP’s role in collagen proteolysis and tumorigenesis is not yet known. I investigated the role of FAP-dependent collagen proteolysis and ECM remodeling in tumorigenesis using both a spontaneous oncogenic Kras-driven lung tumor model and fibroblast-derived matrices. I found that Fap genetic deletion promotes intratumoral fibrillar collagen accumulation and attenuates lung tumor multiplicity, size, progression, and proliferation. Furthermore, I obtained preliminary evidence that Fap-/- lung fibroblasts produce ECM with enhanced fibrillar collagen accumulation, which directly impedes both tumor cell proliferation and motility. Taken together, my research underscores the essential role of ECM remodeling in regulating key aspects of tumorigenesis, such as intratumoral fibroblast heterogeneity, proliferation, and invasion. v TABLE OF CONTENTS DEDICATION ................................................................................................................. II ACKNOWLEDGMENT ...................................................................................................III ABSTRACT................................................................................................................... IV LIST OF FIGURES ...................................................................................................... VIII LIST OF TABLES .......................................................................................................... X CHAPTER ONE: INTRODUCTION ................................................................................ 1 The analogy between tumor stroma generation and wound healing ........................ 1 Fibroblast activation protein (FAP): Structure and function ..................................... 2 FAP as a therapeutic target in the tumor microenvironment ...................................
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