Chemical Biology Screen Reveals Metabolic Heterogeneity During Collective Invasion Open Access
Commander, Rachel (Spring 2020)
Abstract
Phenotypic heterogeneity exists within collectively invading packs of tumor cells, suggesting that cellular subtypes cooperate to drive invasion and metastasis. Here, we take a chemical biology approach to probe cell:cell cooperation within the lung cancer collective invasion pack. We perform the first chemical biology screen on specific leader and follower cellular subtypes and find that leader cells are resistant to most compounds. However, leader cells are more sensitive than follower cells to the antibiotic agents alexidine dihydrochloride, chlorhexidine dihydrochloride, and dequalinium chloride. We characterize the top hit in our screen, alexidine dihydrochloride, as a potent inhibitor of collective invasion. Within collective invasion packs, we observe that leader cells preferentially utilize mitochondrial respiration and trailing follower cells rely on elevated glucose uptake. We define a pyruvate dehydrogenase (PDH) dependency in leader cells that can be targeted therapeutically using alexidine dihydrochloride. Taken together, this work reveals metabolic heterogeneity within the lung cancer collective invasion pack and establishes a rationale for exploiting the dependency of highly invasive cells on PDH activity to inhibit collective cancer cell invasion.
Table of Contents
Chapter 1. Introduction
1.1 Cancer metastasis
1.2 Collective invasion
1.3 Intratumor heterogeneity
1.4 Metabolic heterogeneity
1.5 Dissertation goals
Chapter 2. Chemical biology screen identifies leader cell sensitivity to alexidine dihydrochloride
2.1 Introduction
2.2 Methods
2.3 Results
2.4 Discussion
Chapter 3. Pyruvate dehydrogenase modulation drives invasive phenotype switching
3.1 Introduction
3.2 Methods
3.3 Results
3.4 Discussion
Chapter 4. Conclusions and Future Directions
4.1 Leader cells represent a drug resistant subpopulation
4.2 Metabolic heterogeneity facilitates collective invasion
References
About this Dissertation
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