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Role of Stromal Caveolin-1 (CAV1) Levels in Breast Cancer Angiogenesis

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Role of Stromal Caveolin-1 (CAV1) Levels in Breast Cancer Angiogenesis Universidad Autónoma de Madrid Programa de Doctorado en Biociencias Moleculares Role of stromal Caveolin-1 (CAV1) levels in breast cancer angiogenesis Alberto Díez Sánchez Madrid, 2018 0 1 Departamento de Bioquímica Facultad de Medicina Universidad Autónoma de Madrid Role of stromal Caveolin-1 (CAV1) levels in breast cancer angiogenesis Doctorando: Alberto Díez Sánchez, Licenciado en Biotecnología Director: Miguel Ángel del Pozo Barriuso, MD, PhD. Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Madrid, 2018 1 2 CERTIFICADO DEL DIRECTOR DE TESIS El doctor Miguel Ángel del Pozo Barriuso CERTIFICA que el doctorando Alberto Díez Sánchez ha desarrollado y concluido su trabajo de tesis doctoral “Role of stromal Caveolin-1 (CAV1) levels in breast cancer angiogenesis” bajo su supervisión, en el Centro Nacional de Investigaciones Cardiovasculares (CNIC). Y para que así conste lo firma en Madrid, a 10 de Julio de 2018, Fdo. Dr. Miguel Ángel del Pozo Barriuso Centro Nacional de Investigaciones Cardiovasculares (CNIC) 3 4 ACKNOWLEDGMENTS It is said that scientific knowledge is built on top of the shoulder of giants, in more practical terms, I consider all these people below my personal giants. First ones I encountered, were my parents and grandparents, everything I have achieved has been done on top of their previous efforts, to them I dedicate my most sincere gratitude for teaching this once lazy kid the value of effort. Next, I have to thank all those high-school teachers and university professors that during my education have been able to spark in me the sense of amazement derived from understanding how nature works. Special acknowledgments to my high school biology teacher Charo Díaz, who was able to amazingly convey and share her enthusiasm for her teachings, you are guilty of my choice for biological sciences. While instigating this interest was crucial in my career, a very different scenario was maintaining and nurturing it. Here I would like to thank all those good mentors I have come across during my short lab years: Luis Ángel Fernández (CNB), Marilyn G. Farquhar (UCSD), Mehul Shah (UCSD), Geir Bjørkøy (NTNU)... In this regard, I am especially grateful to my thesis director, Miguel Ángel del Pozo (CNIC), for giving me enough freedom to seek my own questions, make my own mistakes and having the patience of, afterward, dealing with them. On a day to day basis, I am grateful for the people that I have been sharing my bench floor with (both in Spain and in Norway); talking about, most usually, the disappointment of failing experiments and, less commonly, the excitement for a major breakthrough has made my passage through these thesis years much easier and funnier than anticipated. Finishing this period with a good feeling is because of you. In terms of heavy-lifting work, I am grateful for having Mauro, Inés, and Miguel by my side. All the work presented here today would not have been possible without your key contributions. I do not forget my collaborators, in image analysis (Xenia, Daniel, and Laura), high-content screening (Irene and Mariano) and bioinformatics analysis, your abilities do not cease to amaze me. On a personal level, I feel blessed with my lifelong neighborhood friends, not only because of the countless hours of fun that have made easier dealing with lab stress, but also for their continuous support. Without deserving it, they have been calling me “doctor” even before starting my degree. This one is for you. 5 Last but not least, a very special thanks to Mara, my life partner, who has been lately dealing with my stress-related mood swings using an infinite amount of patience and unconditional love. You have made this possible and I cannot wait to have more of yourself for the years to come. This doctoral thesis was made possible with the funding of Obra Social “la Caixa” 6 SUMMARY Tumors have been described as “wounds that never heal”; and non-tumoral surrounding cell populations involved in angiogenesis and response to injury, such as endothelial cells, immune cells and fibroblasts are actively engaged to support the aberrant growth and remodeling of the tumor mass, which conversely determine tumor architecture and behavior. These cells, along with extracellular matrix (ECM) components, define the tumor microenvironment or tumor stroma. While breast cancer progression was conceived for a long time to be largely dependent on aberrant mutations in tumor cells, stromal Cancer-Associated Fibroblasts (CAFs) have been demonstrated to modulate breast cancer growth, invasion, metastasis and therapeutic resistance. Caveolin-1 (CAV1), a prominent organizer of plasma membrane properties and function, exhibits extensive ties with many events defining tumor onset and progression. Although previous studies have shown CAV1 expression levels in CAFs to influence breast cancer growth and metastasis, the underlying driving mechanisms remain incompletely characterized. In this regard, ECM modification and metabolic reprogramming have been proposed as key aspects of a stromal CAV1-dependent role in tumor biology. This thesis research report aims to contribute to our understanding as to how CAV1 expression in stromal CAFs impact tumor angiogenesis, and thus tumor hypoxia, cancer aggressiveness and metastasis. The present work showcases evidence supporting a positive reciprocal feedback relationship between stromal CAV1 downregulation and endoplasmic reticulum (ER) stress, which can drive exacerbated proangiogenic signaling, causative of the generation of an aberrant and dysfunctional tumor vasculature. This report proposes defective angiogenesis and consequent hypoxia as major driving causes for increased aggressiveness of breast cancer in low stromal CAV1 tumors. 7 RESUMEN Los tumores podrían describirse como heridas que nunca terminan de curarse. En respuesta a esta agresión, se puede observar el reclutamiento de células del sistema inmune, de fibroblastos que intentan cerrar la lesión y de células endoteliales implicadas en la formación de nuevos vasos sanguíneos y linfáticos. Estas células, en conjunto con la matriz extracelular (ECM, Extracellular Matrix, por sus siglas en inglés) que las rodea, conforman lo que se conoce como microambiente o estroma tumoral. Durante décadas, la progresión y el comportamiento del cáncer de mama se concebían como procesos dependientes de las mutaciones que acaecían en las células tumorales. Sin embargo, recientemente varios estudios han demostrado que el microambiente tumoral en general, y los fibroblastos estromales asociados al tumor (CAFs, Cancer-Associated Fibroblasts, por sus siglas en inglés) en particular, son capaces de modular el crecimiento tumoral, la capacidad invasiva y el proceso metastático del cáncer de mama, así como la resistencia a determinadas terapias. Aunque estudios previos han demostrado que los niveles de la proteína Caveolina-1 (CAV1) que presentan los fibroblastos estromales (CAFs) tienen una influencia sobre la capacidad metastática y de crecimiento del cáncer de mama, el mecanismo responsable de esta habilidad moduladora está por resolver. Procesos como la modificación ejercida por estos CAFs sobre la ECM y su potencial para reprogramar el metabolismo tumoral se han postulado como piezas de este rompecabezas. Este trabajo describe como una bajada en la expresión de CAV1 en CAFs estromales orquestra la formación de una vasculatura tumoral disfuncional y aberrante que resulta en un incremento de la hipoxia, la agresividad y la capacidad metastática de estos tumores con bajos niveles de CAV1 estromal. Además, establece un círculo vicioso de retroalimentación positiva entre la menor expresión de CAV1 y la inducción de estrés reticular, que en última instancia es responsable de la activación de una señalización proangiogénica exacerbada que deriva en la formación de la vasculatura aberrante arriba mencionada. 8 INDEX ACKNOWLEDGMENTS ....................................................................................................... 5 SUMMARY ............................................................................................................................ 7 RESUMEN ............................................................................................................................ 8 NON-STANDARD ABBREVIATIONS AND ACRONYMS ....................................................13 1A. INTRODUCTION ...........................................................................................................19 1.1 Breast Cancer: an overview .....................................................................................20 1.1.1 Breast Anatomy and Physiology ...........................................................................20 1.1.2 Classification of Breast Cancers ...........................................................................21 1.1.3 Triple Negative Breast Cancer (TNBC) .................................................................24 1.2 Tumor Microenvironment (TME) / Tumor Stroma ...................................................25 1.2.1 Immune Suppression and Tumor-Associated Macrophages (TAMs) ....................26 1.2.2 Cancer-Associated Fibroblasts (CAFs) .................................................................27 1.3 Tumor Angiogenesis ................................................................................................30 1.3.1 Alternative Modes of Tumor Vascularization .........................................................32 1.3.2 Microenvironmental Regulation of Tumor
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