Insulin-like Growth Factor Regulation of Nutrition-Dependent Growth, Regeneration, and Tumorigenesis
ORCID
https://orcid.org/0000-0001-8789-9706
Date of Award
1-10-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The nutrition-dependence of vertebrate growth is context-dependent. In most cases, starvation arrests growth; however, regenerating tissues and tumors generally exhibit nutrition-independent growth. Why starvation halts ontogenic growth but not regeneration in the fish fin is a longstanding paradox first described by Thomas Hunt Morgan in 1906. We investigated the role of glucose metabolism in Morgan’s paradox, proposing that regenerating tissues gain access to glucose during starvation and that starving non-regenerating tissues lose access to glucose—a model we termed “glucose licensing.” Measuring glucose metabolism in vivo during starvation without perturbing the metabolism under measurement required analysis of the glucose analog 2-deoxyglucose (2DG) and its intracellular metabolite, 2-deoxyglucose 6-phosphate (2DG6P), which were difficult to quantitatively resolve with commonly-used metabolomics methods at the time. We developed new chromatography methods with broader coverage of polar metabolites by shielding high-affinity electrostatic interactions between analytes and the column, using a zwitterionic stationary phase and a mobile phase salt mixture containing trace phosphate. Using this method to measure 2DG and 2DG6P, we found fins in starvation-induced growth arrest reduced glucose uptake by ~70%, while regenerating fins increased glucose uptake ~200% regardless of nutrition state, consistent with our “glucose licensing model.” Nevertheless, the magnitude of these changes indicated that starvation-induced growth arrest was not mediated directly by circulating metabolite levels, leading us to hypothesize that a systemic nutrition signal and local regenerative bypass signal cause the different states of growth and glucose uptake observed in Morgan’s paradox. Postulating the necessary functional properties of these signals and considering transcriptional data from fins in different growth states led us to further hypothesize that insulin-like growth factor 1 (IGF-1) systemically regulates nutrition-dependent growth, while IGF-2 drives regenerative bypass of systemic nutrition-dependence. Pilot experiments using glucose uptake as an indirect growth assay suggested that exogenous IGF-1 can override nutrition state and that the rate of regeneration is sensitive to IGF signaling. We then became interested in whether our model of IGF-1 control of nutrition-dependent growth could explain a dual paradox in cancer, in which spontaneous cancer onset is nutrition-dependent and absent in humans with genetic GH/IGF-1 signaling deficiency, but fasting or pharmacologically inhibiting GH/IGF-1 signaling in patients with established cancer fails to substantially improve treatment outcomes. Based on the pro-survival effects of IGF-1 signaling and postulating that apoptotic pressure is likely maximal at the earliest stages of tumor development, we proposed a timing-based hypothesis, in which cancer primarily is dependent on systemic IGF-1 during the initiation phase. Using a zebrafish crestin:EGFP model to visualize melanoma development, we found that early tumors were highly sensitive to nutrition and IGF-1 signaling but rapidly became fasting resistant as they grew. Genetically blocking IGF-1 signaling via GH loss of function caused near-complete inhibition of melanoma initiation, while overactivating melanocyte-specific IGF1R signaling reversed this effect. GH loss of function also prevented spontaneous tumor development caused by random mutations in p53-deficient zebrafish. These findings suggest that IGF-1 has distinct effects on different stages of tumor development, which may contribute to fasting’s differing effectiveness for reducing cancer incidence versus treating established tumors.
Language
English (en)
Chair and Committee
Gary Patti
Committee Members
Charles Kaufman
Recommended Citation
Spalding, Jonathan Lamouth, "Insulin-like Growth Factor Regulation of Nutrition-Dependent Growth, Regeneration, and Tumorigenesis" (2024). Arts & Sciences Electronic Theses and Dissertations. 3229.
https://openscholarship.wustl.edu/art_sci_etds/3229