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Regulation of Mmp2/9 Transport to the Invadopodia

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Regulation of Mmp2/9 Transport to the Invadopodia REGULATION OF MMP2/9 TRANSPORT TO THE INVADOPODIA DURING BREAST CANCER CELL INVASION by ABITHA JACOB B.S., Monash University, 2005 M.S., University of Dundee, 2007 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Molecular Biology Program 2016 This thesis for the Doctor of Philosophy degree by Abitha Jacob has been approved for the Molecular Biology Program by Andrew Bradford, Chair Heide Ford Paul Jedlicka Mary Reyland Traci Lyons Rytis Prekeris, Advisor Date 05-20-2016 ii Jacob, Abitha (Ph.D., Molecular Biology) Regulation of MMP2/9 Transport to the Invadopodia During Breast Cancer Cell Invasion Thesis directed by Professor Rytis Prekeris ABSTRACT Invadopodia-dependent degradation of the basement membrane plays a major role during metastasis of breast cancer cells. Basement membrane degradation is mediated by targeted secretion of various matrix metalloproteinases (MMPs). Specifically, MMP2 and MMP9 possess the ability to hydrolyze components of the basement membrane and were shown to regulate various aspects of tumor growth and metastasis. However, the membrane transport machinery that mediates MMP2/9 targeting to the invadopodia during cancer cell invasion remains to be defined. Rab GTPases are master regulators of intracellular vesicle transport. Here, we identify and characterize the role of Rab40b GTPase as a protein required for secretion of MMP2/9. Using a combination of shRNA based protein knockdown in MDA-MB-231 breast cancer cells with fluorescent microscopy and in situ zymography, we report that Rab40b is required for MMP2/9 sorting into VAMP4-containing secretory vesicles. We identify Rab40b as novel mediator for the targeting of MMP2/9 secretory vesicles to the forming invadopodia and is required for invadopodia-dependent extracellular matrix degradation. Furthermore, we demonstrate that Rab40b is also required for breast cancer cell invasion in vitro. Using a 3D invasion and spheroid culture system, we show that the results we obtained from the 2D system is relevant in a 3D system that simulates the in vivo environment better. Following our analysis of Rab40b in MDA-MB-231 cells, we sought to determine whether Rab40b regulates breast cancer cell invasion in vivo. Utilizing shRNA based stable iii knockdown cell lines and a mouse mammary fat pad injection model, we demonstrate the role of Rab40b in primary tumor growth and metastasis. We show that Rab40b depletion results in reduced primary tumor size, possibly due to decreased angiogenesis and also lack invasion and cell dispersal. Additionally, we show decreased micro-metastases in the mouse lung upon depletion of Rab40b. Taken together, our data suggest that Rab40b decreases tumor growth and metastasis, potentially as a direct result of cancer cell invasion as well as effects on primary tumor angiogenesis. We also demonstrate that Rab40b functions by interacting with Tks5, a known Src kinase substrate and invadopodia-regulating protein. Significantly, the expression of Rab40b is increased in highly metastatic basal breast tumors, and we demonstrate that Rab40b and Tks5 levels are regulated by miR-204. We show that miR-204 is involved in down-regulating Rab40b and Tks5, thus inhibiting MMP2/9 targeting to invadopodia resulting in a decrease in invadopodia-associated ECM degradation. This is the first study that identifies and defines a novel Rab40b/Tks5 and miR-204 dependent invadopodia transport pathway that regulates MMP2/9 secretion and extracellular matrix remodeling during breast cancer progression both in vitro and in vivo. The form and content of this abstract are approved. I recommend its publication. Approved: Rytis Prekeris iv TABLE OF CONTENTS CHAPTER I. THE ROLE OF MMPS AND INVADOPODIA DURING CANCER CELL INVASION AND METASTASIS ..........................................................1 Abstract ........................................................................................................1 The role of invadopodia in cancer cell invasion ..........................................2 Stages of invadopodia formation .................................................................4 Initiation ...........................................................................................4 Assembly..........................................................................................5 Maturation ........................................................................................6 Invadopodia formation and function in vivo ................................................7 The role of matrix metalloproteinases in cancer cell metastasis ..................8 Mechanisms mediating MMP targeting to invadopodia ............................11 Targeting of MMP14 ....................................................................12 Targeting of MMP2 and MMP9 ...................................................15 Conclusions and future objectives .............................................................16 II. RAB40B REGULATES MMP2 AND 9 TARGETING TO THE INVADOPODIA DURING BREAST CANCER CELL INVASION ............17 Abstract ......................................................................................................17 Introduction ................................................................................................18 Materials and methods ...............................................................................20 Antibodies and constructs ..............................................................20 Cell culture and tet-inducible MDA-MB-231 lines. ......................21 siRNA library screen......................................................................21 v Elisa assays ....................................................................................22 In vitro invasion and motility assays .............................................22 Fluorescent microscopy .................................................................23 FACS analysis ................................................................................24 Zymography assays ........................................................................25 In situ zymography assays .............................................................25 Reverse transcriptase PCR and quantitative PCR ..........................26 Flow cytometry based GFP-hGH secretion assay .........................27 Statistical analyses .........................................................................28 Results .......................................................................................................28 Rab40b GTPase is required for MMP2 and MMP9 secretion .......28 Rab40b is required MMP2 and MMP9 sorting and secretion .......33 Rab40b is localized to VAMP4 containing secretory vesicles ......36 Rab40b is required for breast cancer cell invasion and invadopodia dependent ECM degradation in vitro ........................41 Discussion ..................................................................................................47 III. THE ROLE AND REGULATION OF RAB40B/TKS5 COMPLEX IN MMP TARGETING AND CANCER CELL INVASION ..............................52 Abstract ......................................................................................................52 Introduction ................................................................................................53 Materials and Methods ...............................................................................55 Antibodies and constructs ..............................................................55 Cell lines ........................................................................................56 GST-Rab40b affinity chromatography ..........................................56 vi GST-Tks5 fragments and glutathione bead pull-down assay ........57 Molecular modeling .......................................................................57 Inverse inversion assay ..................................................................58 In situ zymography ........................................................................58 RT-PCR and qPCR ........................................................................59 Luciferase assay .............................................................................60 3D spheroid assay ..........................................................................60 Mouse mammary fat pad xenograft assays ....................................61 In situ analysis of lung metastasis ..................................................62 Immunohistochemistry ..................................................................62 Breast cancer data mining ..............................................................63 Results……………………………………………………………………63 Rab40b is required for breast cancer cell invasion and invadopodia extension ...................................................................63 Rab40b is required for primary tumor growth and metastasis in vivo .............................................................................................73 Tks5 is a Rab40b binding protein that regulates invadopodia function ..........................................................................................79 miR-204 regulates expression of Rab40b and Tks5 expression breast cancer cells ..........................................................................83 Discussion ..................................................................................................88
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