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Lim Washington 0250E 22623.Pdf (6.315Mb) © Copyright 2021 Andrea Lim Mechanisms of tumor dormancy and awakening in the lymph node Andrea Lim A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2021 Reading Committee: Cyrus M. Ghajar, Chair Peggy Porter Slobodan Beronja Program Authorized to Offer Degree: Molecular and Cellular Biology University of Washington Abstract Mechanisms of tumor dormancy and awakening in the lymph node Andrea Lim Chair of the Supervisory Committee: Cyrus M. Ghajar, Ph.D. Public Health Sciences Division, Fred Hutchinson Cancer Research Center Mechanisms of tumor dormancy are being systematically uncovered through the major organs. Yet little is known about lymph nodes (LNs) as harbors of residual disease, despite their well-established prognostic significance for metastasis and direct contribution to metastasis in visceral organs. Further, few mechanisms of awakening from dormancy have been reported. To investigate tumor dormancy in the LN, the niche for dormant disseminated tumor cells (DTCs) was characterized by spatial analysis of LN tissues from a model of spontaneous murine mammary carcinoma dissemination to the lymph node. Ki-67- DTCs were significantly enriched near blood endothelia but not lymphatic endothelia versus a null distribution control, revealing that the lymph node blood vasculature is the primary niche for quiescent DTCs. An organotypic co-culture model of the LN vascular niche was developed to study the mechanisms underlying niche regulation of tumor quiescence. Human breast cancer cell line HMT-3522-T4-2 were growth suppressed in the presence of endothelial cells, recapitulating the effect of the vascular niche in vivo. RNA sequencing revealed that TGFβ signaling was among the most differentially upregulated pathways in the niches containing blood endothelial cells, which was validated through ELISA. Addition of TGF-β1 to tumor growth-permissive LN stromal cultures suppressed tumor cell growth as seen in vascular niches, providing evidence that TGF-β1 promotes DTC quiescence in the LN vascular niche. To investigate tumor awakening in the LN, the stable vascular niche was disrupted through sustained inflammation via bacterial lipopolysaccharide (LPS), which resulted in endothelial remodeling and LN expansion. LPS treatment of mice with LN DTCs resulted in over ten-fold increase in LN micrometastases, supporting the emerging theme that tissue dysregulation and loss of homeostasis triggers metastatic outgrowth. The inflamed stroma was transcriptionally profiled using single-cell RNA sequencing, which revealed that expression of the TGFβ pathway decreased upon inflammation. Knocking down requisite TGFβ receptor 2 in tumor cells enhanced micrometastatic outgrowth within the LN, supporting the hypothesis that blood endothelial-derived TGF-β1 is required for DTC quiescence. These studies reveal that the LN supports DTC dormancy and provide evidence that endothelial TGF-β1 promotes quiescence in the vascular niche. Further, inflammation is sufficient to induce micrometastatic outgrowth in the LN, concomitant with stromal remodeling and loss of endothelial TGFβ expression. TABLE OF CONTENTS Chapter 1. General Introduction ..................................................................................................... 1 1.1 Breast cancer at the primary site ..................................................................................... 2 1.2 Breast cancer metastasis ................................................................................................. 5 Chapter 2. Tumor Dormancy ........................................................................................................ 10 2.1 Defining dormancy ....................................................................................................... 11 2.2 Evidence for tumor dormancy in disease ...................................................................... 14 Chapter 3. Tissue-specific determinants of dormancy and awakening......................................... 17 3.1 Bone .............................................................................................................................. 19 3.2 Lung .............................................................................................................................. 29 3.3 Brain .............................................................................................................................. 35 3.4 Liver .............................................................................................................................. 40 3.5 Lymph node .................................................................................................................. 47 Chapter 4. The lymph node niche for dormant disseminated tumor cells .................................... 52 4.1 Introduction ................................................................................................................... 52 4.2 Results ........................................................................................................................... 53 4.3 Discussion ..................................................................................................................... 58 Chapter 5. Deconstructing the lymph node endothelial niche ...................................................... 60 5.1 Introduction ................................................................................................................... 60 v 5.2 Results ........................................................................................................................... 61 5.3 Discussion ..................................................................................................................... 74 Chapter 6. Tissue dysregulation in the inflamed lymph node precedes metastatic outgrowth ..... 76 6.1 Introduction ................................................................................................................... 76 6.2 Results ........................................................................................................................... 77 6.3 Discussion ..................................................................................................................... 93 Chapter 7. Conclusions and future directions ............................................................................... 96 Chapter 8. Materials and methods .............................................................................................. 102 8.1 Animal studies ............................................................................................................ 102 8.2 Cell Culture ................................................................................................................. 104 8.3 Cell culture assays....................................................................................................... 108 8.4 Analysis of lymph node microvascular niches via LC-MS/MS. ................................ 109 8.1 RNA sequencing ......................................................................................................... 110 8.2 Single-cell RNA sequencing of LN stromal cells ....................................................... 110 8.3 Immunofluorescence ................................................................................................... 112 8.4 Immunohistochemistry ............................................................................................... 114 8.5 Western blot ................................................................................................................ 114 8.6 Image Analysis............................................................................................................ 116 8.7 Statistical Analysis ...................................................................................................... 117 8.8 Antibodies ................................................................................................................... 118 Bibliography………………………………………………………………………………….121 vi LIST OF FIGURES Figure 1. Classical view of the metastatic cascade. 7 Figure 2. The bone marrow microenvironment for dormant DTCs. 21 Figure 3. The lung microenvironment for dormant DTCs. 32 Figure 4. The brain microenvironment for dormant DTCs. 37 Figure 5. The liver microenvironment for dormant DTCs. 44 Figure 6. The lymph node microenvironment for dormant DTCs. 51 Figure 7. An orthotopic model for spontaneous dissemination reveals that the lymph 55 node harbors 4T07 DTCs in lymphovascular regions. Figure 8. Illustration of the cellular organization of the lymph node. 55 Figure 9. Quiescent lymph node DTCs demonstrate a preference for the vascular niche. 56 Figure 10. A randomly generated point distribution serves as a null control for DTC 57 localization in the lymph node. Figure 11. A second orthotopic model shows similar trends of blood vessel enrichment 58 for D2.0R DTCs. Figure 12. An organotypic co-culture model of the lymph node endothelial niche. 62 Figure 13. Tumor cell growth on lymph node microvascular niches. 64 Figure 14. Characterization of lymph node MVNs by targeted ECM proteomics. 65 Figure 15. RNAseq analysis of lymph node MVNs revealed differentially expressed 66 targets in each endothelial condition, versus the FRC alone condition. Figure 16. Panel of ECM targets of interest that stained positively in lymph node MVNs. 67 Figure 17. TINAGL1 is expressed in the lymph node
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