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Defining the Role of CD109 in Modulating TGF-Β and EGFR

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Defining the Role of CD109 in Modulating TGF-Β and EGFR Defining the Role of CD109 in Modulating TGF- and EGFR Signaling in Squamous Cell Carcinoma by Shufeng Zhou Department of Surgery Division of Experimental Surgery McGill University, Montreal, Quebec, Canada A thesis submitted to the Faculty of Graduate and Postdoctoral Studies in partial fulfillment of the requirements for the Degree of Doctor of Philosophy. © Copyright by Shufeng Zhou March 2019 TABLE OF CONTENTS TABLE OF CONTENTS………………………………………………………………………..ii LIST OF FIGURES, SCHEMES AND TABLES.....................................................................viii ABSTRACT..................................................................................................................................xi RÉSUMÉ.....................................................................................................................................xiv ACKNOWLEDGEMENTS......................................................................................................xvii CONTRIBUTIONS TO ORIGINAL KNOWLEDGE............................................................xx PREFACE AND CONTRIBUTION OF AUTHORS ………………...................................xxiv ABBREVIATIONS ..................................................................................................................xxvi CHAPTER I: INTRODUCTION.................................................................................................1 I.1 Overview of cancer ……………………………………………………………………..........2 I.1.1 Squamous cell carcinoma (SCC)..........................................................................................2 I.1.1.1 Cutaneous squamous cell carcinoma (CSCC)………………………………………….3 I.1.1.2 Head and neck squamous cell carcinoma (HNSCC)…………………………………..3 I.1.1.3 Common molecular markers of SCCs………………………………………………….5 I.1.2 Heterogeneity of Cancer……………………………………………………………………7 I.1.2.1 Clonal evolution theory…………………………………………………………………8 I.1.2.2 Cancer stem cell (CSC) model………………………………………………………….9 I.2 Cancer stem cells (CSCs)……………………………………………………………………11 I.2.1 The discovery of cancer stem cells………………………………………………………..11 I.2.2 Functional traits of CSCs…………………………………………………………………11 I.2.3 The Origin of cancer stem cells…………………………………………………………..15 I.2.4 Identification of cancer stem cells markers ……………………………………………..16 ii I.2.4.1 Pluripotential stem markers……………………………………………………………..17 I.2.4.2 Cancer stem cell markers ……………………………………………………………….19 I.2.4.3 Detection of cancer stem cells: in vitro and in vivo assays……………………………..21 I.3 Metastasis …………………………………………………………………………………...21 I.3.1 Local invasion……………………………………………………………………………...22 I.3.2. Intravasation……………………………………………………………………………...23 I.3.3 Survival in the Circulation……………………………………………………………….24 I.3.4 Arrest at a distant organ site……………………………………………………………..25 I.3.5 Extravasation……………………………………………………………………………...25 I.3.6 Survival in a remote microenvironment to form micrometastases ……………………26 I.3.7 Metastatic Colonization…………………………………………………………………...26 I.3.8 Hypothesis for Metastasis…………………………………………………………………27 I.4 Epithelial to Mesenchymal Transition (EMT)…………………………………………….30 I.4.1 Categories of EMT………………………………………………………………………...31 I.4.1.1 Type 1 EMT……………………………………………………………………………31 I.4.1.2 Type 2 EMT……………………………………………………………………………31 I.4.1.3 Type 3 EMT……………………………………………………………………………32 I.4.2 Regulation of EMT………………………………………………………………………..32 I.4.2.1 EMT effectors…………………………………………………………………………32 I.4.2.2 EMT core regulators…………………………………………………………………..33 I.4.2.3 EMT inducers - extracellular signals………………………………………………….36 I.4.3 MicroRNAs-mediated regulation of EMT……………………………………………….38 I.4.4 EMT and Stemness………………………………………………………………………..39 iii I.4.5 EMT and Metastasis………………………………………………………………………41 I.5 The transforming growth factor-beta (TGF-) signaling pathway……………………….43 I.5.1 TGF-β superfamily………………………………………………………………………..44 I.5.2 TGF-β receptors…………………………………………………………………………...46 I.5.3 TGF-/Smad canonical signaling pathway………………………………………………47 I.5.4 Non-Smad TGF- pathways……………………………………………………………...48 I.5.5 TGF- in cancer - Dual role of TGF-β as a tumor suppressor and promoter…………………48 I.5.6 TGF-β in immune suppression/evasion………………………………………………….49 I.5.7 TGF-β and angiogenesis…………………………………………………………………..50 I.5.8 The Roles of TGF-β in EMT, Cancer stem cells and Metastasis ………………………50 I.6 The Epidermal Growth Factor Receptor (EGFR)…………………………………………52 I.6.1 The structure of EGFR……………………………………………………………………53 I.6.2 The activation of EGFR…………………………………………………………………...55 I.6.3 EGFR downstream signal………………………………………………………………...55 I.6.3.1 KRAS-BRAF-MEK/ERK signaling pathway………………………………………….56 I.6.3.2 PI3K/AKT pathway……………………………………………………………………56 I.6.4 EGFR in cancer……………………………………………………………………………57 I.7 CD109………………………………………………………………………………………..58 I.7.1 The structure of CD109 ………………………………………………………………….59 I.7.2 The processing and isoforms of CD109………………………………………………….60 I.7.3 CD109 in TGF- signaling ……………………………………………………………….61 I.7.4 CD109 in EGFR signaling………………………………………………………………..63 I.7.5 CD109 in Cancer………………………………………………………………………….64 iv I.8 Rationale and objectives for the current study…………………………………………..65 I.9 Reference …………………………………………………………………………………..69 Connecting Text 1…………………………………………………………………………….104 CHAPTER II--MANUSCRIPT 1: CD109 released from human bone marrow mesenchymal stem cells attenuates TGF-β-induced epithelial to mesenchymal transition and stemness of squamous cell carcinoma……………………………………………………………………...105 II.1 Abstract…………………………………………………………………………………….106 II.2 Introduction ………………………………………………………………………………..107 II.3 Results ……………………………………………………………………………………..109 II.4 Discussion……………………………………………………………………………………116 II.5 Materials and methods……………………………………………………………………………….120 II.6 Conclusion…………………………………………………………………………………...124 II.7 References……………………………………………………………………………………………125 II.8 Figures and Supplementary Materia …………………………………………………………………130 Connecting Text 2……………………………………………………………………………..140 CHAPTER III-MANUSCRIPT 2: CD109 acts as a gatekeeper of the epithelial trait by suppressing epithelial to mesenchymal transition in squamous cell carcinoma cells in vitro…………………………………………………………………………………………….141 III.1 Abstract……………………………………………………………………………………142 III.2 Introduction ……………………………………………………………………………….143 III.3 Results…………………………………………………………………………………….144 III.4 Discussion…………………………………………………………………………………153 v III.5 Materials and methods…………………………………………………………………….156 III.6 References…………………………………………………………………………………165 III.7 Figures and Supplementary Materia………………………………………………………………..169 Connecting Text 3……………………………………………………………………………..182 CHAPTER IV- MANUSCRIPT 3: CD109 Drives Tumorigenesis and Metastasis by Modulating the EGFR/Akt Signaling in Squamous Cell Carcinoma………………………183 IV.1 Abstract……………………………………………………………………………………184 IV.2 Introduction………………………………………………………………………………..185 IV.3 Results……………………………………………………………………………………..187 IV.4 Discussion…………………………………………………………………………………197 IV.5 Materials and methods…………………………………………………………………….200 IV.6 References…………………………………………………………………………………………..209 IV.7 Figures and Supplementary Materia………………………………………………………………..213 CHAPTER V- DISCUSSION, CONCLUSIONS AND PERSPECTIVES………………..226 V.1 Soluble CD109 suppresses the motility, invasion and stemness of SCC cells by inhibiting the TGF-β-induced EMT in vitro…………………………………………………………227 V.2 CD109 acts as a gatekeeper of the epithelial phenotype in SCC cells by regulating the TGF- pathway…………………………………………………………………………….228 V.3 CD109 acts as a driving force of tumorigenesis and metastasis by modulating the EGFR/AKT signaling in squamous cell carcinoma……………………………………….230 V.4 CD109 is a novel putative therapeutic target in cancer……………………………………233 V.5 Concluding remarks and future perspectives………………………………………………234 vi V.6 References………………………………………………………………………………….236 Appendix……………………………………………………………………………………….239 vii LIST OF FIGURES, SCHEMES AND TABLES CHAPTER I-INTRODUCTION Figure 1 Tumor growth models………………………………………………………………….10 Figure 2 The two CSC models…………………………………………………………………..14 Figure 3 The two mechanisms of cancer cell dissemination…………………………………….23 Figure 4 The invasion–metastasis cascade………………………………………………………27 Figure 5 The evolving concept of mCSCs………………………………………………………29 Figure 6 Metastasis model with hybrid E/M cells………………………………………………..43 Figure 7 Members of the TGF-β family…………………………………………………45 Figure 8 The canonical model of EGFR structure and activation………………………………..54 Figure 9 Schematic elucidation of EGFR downstream signal pathways…………………………55 Figure 10 Schematic representation of CD109 domains…………………………………………60 Figure 11 Schematic representation of CD109 function…………………………………………63 Table 1 TGF-β receptors and their binding ligands………………………………………………47 CHAPTER II - MANUSCRIPT 1 Figure 1 hBM-MSC-CM exhibits anti-proliferation and pro-apoptosis effect on SSCs……….130 Figure 2 hBM-MSC-CM decreases EMT traits of SCCs……………………………………….131 Figure 3 hBM-MSC-CM inhibits the migration and invasiveness of SCCs…………………….132 Figure 4 hBM-MSC-CM decreases SOX2 expression and tumor spheres formation…………..133 Figure 5 Knockdown of CD109 by targeted siRNA in hBM-MSCs significantly abrogated the anti-migration and anti-invasion of hBM-MSC-CM………………………………………134 Figure 6 The effect of the overexpression of CD109 on A431 cells……………………………135 Figure 7 A schematic model depicting the possible mechanism underlying the anti-cancer viii effect of hBM-MSCs-CM………………………………………………………………………136 Supplementary Figure 1 The effect of hBM-MSCs-CM on FaDu, a model cell line of head and neck squamous cell carcinoma………………………………………………………………….137
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