BioE PhD Defense Presentation- Isaac Robinson

Advisor:

Prof. Adam Marcus (School of Medicine, Winship Cancer Institute, Emory University)

Committee:

Prof. Sumin Kang (School of Medicine, Winship Cancer Institute, Emory University)

Prof. Shuichi Takayama (School of Biomedical Engineering, Georgia Institute of Technology)

Prof. Edward Botchwey (School of Biomedical Engineering, Georgia Institute of Technology)

Prof. Andrés García (School of Mechanical Engineering, Georgia Institute of Technology)

Spatiotemporal Interrogation of Metabolic Cooperation in Collective Cell Invasion

Cancer can be characterized by a lack of uniformity. There are the obvious distinctions of cancer type—lung vs prostate vs skin cancers—but even the cancer cells within a single tumor of an individual patient exhibit a variety of mutational and behavioral profiles. This heterogeneity contributes to the successful overall progression of cancer by means of drug resistance and, as we argue here, stress management. Previous work highlights metabolic heterogeneity within the H1299 non-small cell lung cancer (NSCLC) model cell line. One distinct subpopulation within the model, characterized by aggressive invasion, relies heavily on oxidative phosphorylation (OXPHOS) while a second subpopulation, characterized by less invasion but more proliferation, utilizes glycolysis for energy production. Our in-vivo data suggests that, while each subpopulation can independently form primary tumors, the combination of both is required for successful macro-metastasis to peripheral locations. This led us to hypothesize that metabolic heterogeneity in lung cancer enables metabolic cooperation which promotes cancer progression by means of valuable-resource sharing in harsh and otherwise unsustainable, nutrient-scarce microenvironments. To test this hypothesis, we aimed to 1) develop a methodology—incorporating genetic engineering, live-cell, high-resolution microscopy, and common end-point assays—capable of observing and characterizing this metabolic cooperation in NSCLC cells and amenable to simple translation for investigation of other forms of cooperation across cancer types and 2) uncover,  using this methodology, modes and mechanisms of glycolytic and OXPHOS-related cargo sharing within NSCLC. At the forefront of the race to reduce cancer deaths lies a fundamental understanding of how cancer progression and metastasis occur. This body of work provides an adaptable technique for interrogation of this process from a perspective focusing on the cooperative potential that intratumoral heterogeneity affords. It also contributes novel insight into how one specific cancer type makes use of cooperation to overcome obstacles to disease progression.