Lysine demethylase 5B as a mediator of collective invasion translation missing: it.hyrax.visibility.files_restricted.text

Zoeller, Elizabeth (Summer 2019)

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Metastatic disease is the primary cause of death in cancer patients. Therapeutic targeting of the metastatic process has not performed well because of the complexity of the multi-step process and difficulty identifying molecular targets. Recent discoveries point to collective cell invasion, in which a group of cells invade in a coordinated, cooperative manner and can contain distinct functional populations such as cells that lead and cells that follow, as key to successful metastases formation both during the initial invasive steps leaving the primary site and the later establishment of tumors at a distant site. Given the many adaptions to changes in environment required of metastatic cells, survival of these cells depends on plasticity in gene expression, making epigenetic regulators promising anti-metastatic targets. In fact, many inhibitors of epigenetic enzymes are currently in development as anti-cancer treatments. Among these, lysine demethylase 5B (KDM5B) and fellow KDM5 family members are being rigorously investigated in efforts to develop effective and selective inhibitors. KDM5 family members are overexpressed across many cancer types. Moreover, KDM5B has been positively associated with invasive cell behavior in multiple cancers. To clarify the role of KDM5B in collective invasion, we utilized a non-small cell lung cancer model of leader and follower populations isolated from cells invading as a collective chain. Followers expressed less KDM5B overall and a mutant version of KDM5B that was absent from leaders, leading us to hypothesize that intact KDM5B is a requirement of leader cell behavior and decreased KDM5B activity defines follower cells. By measuring invasive behaviors after overexpressing wild-type or mutant KDM5B across leader and follower cells, we found that chain formation was enhanced by the presence of both KDM5B active and KDM5B deficient populations. Next, to determine the feasibility of preventing collective invasion through chemical inhibition of KDM5 enzymes, we tested several compounds in our invasive model. Although we did not successfully identify a treatment protocol against invasive behaviors, KDM5B and family members remain promising anti-metastatic targets. Here we uncover a novel role for KDM5B in collective invasion and take a step towards understanding and preventing the occurrence of metastasis.

Table of Contents

Chapter 1: Introduction

1.1 Metastasis and mortality

1.2 Heterogeneity in cancer

1.3 EMT and the metastatic process

1.4 Collective invasion and the origins of metastatic lesions

1.5 Leader and follower cells

1.6 Epigenetics in cancer

1.7 Functions of the lysine demethylase 5 family

1.8 Roles of lysine demethylase 5B in cancer

1.9 Dissertation goals

Chapter 2: Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes

2.1 Abstract

2.2 Introduction

2.3 Results

2.4 Discussion

Chapter 3: Investigating KDM5B as an anti-metastatic therapeutic target

3.1 Introduction

3.2 Results

3.3 Discussion

Chapter 4: Discussion

4.1 KDM5B as a mediator of collective invasion

4.1.1 Summary of findings

4.1.2 Models of heterogeneity and cooperativity in invasion

4.1.3 Future considerations

4.2 KDM5B as a therapeutic target

4.2.1 Summary of findings

4.2.2 Future considerations

Chapter 5: Materials and methods


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