Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

M. C. Simon

Abstract

Sarcomas are uncommon but diverse mesenchymal malignancies arising from connective tissues, such as muscle, fat and cartilage. Despite rapid advances in molecular understanding of individual subtypes and pathway-specific therapies, the remarkable cellular and genetic heterogeneity of soft tissue sarcomas (STS) limits clinical benefit of targeted treatments. A variety of metabolism-associated oncogenic signaling pathways have been identified in sarcomas. Both these internal and external alterations converge to change cell metabolism, rendering sarcoma cells more susceptible to perturbations within metabolic networks. However, how abnormal metabolism influences sarcoma growth remains understudied.

I show that expression of the gluconeogenic isozyme fructose-1,6-bisphosphatase 2 (FBP2) is silenced in a broad spectrum of STS subtypes, revealing an apparent common metabolic feature shared by diverse STS. Enforced FBP2 re-expression inhibits STS cell and tumor growth through two distinct mechanisms. First, cytosolic FBP2 antagonizes elevated glycolysis associated with the “Warburg effect”, thereby inhibiting sarcoma cell proliferation. Second, nuclear-localized FBP2 restrains mitochondrial biogenesis and respiration in a catalytic activity-independent manner by inhibiting the expression of nuclear respiratory factor (NRF1) and mitochondrial transcription factor A (TFAM). Specifically, nuclear FBP2 colocalizes with the c-Myc transcription factor at the TFAM locus and represses c-Myc-dependent TFAM expression. This unique dual function of FBP2 provides a rationale for its selective suppression in STS, identifying a potential metabolic vulnerability and possible future therapeutic target.

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