Our laboratory is interested in studying how broken tricarboxylic acid (TCA) cycle metabolism can cause cancer. Specifically, we study familial paraganglioma (PGL), a neuroendocrine cancer that is a model for tumorigenesis driven by metabolic derangement. Familial PGL displays an apparent autosomal dominant inheritance pattern resulting from loss of both copies of genes encoding subunits of succinate dehydrogenase (SDH), a TCA cycle enzyme that catalyzes the conversion of succinate to fumarate. The current working model for PGL tumorigenesis involves bi-allelic SDH loss with subsequent accumulation of succinate, which competitively inhibits the activities of several dioxygenase enzymes that demethylate histones and DNA, and suppress hypoxic signaling. This model is supported by observations in human PGL tumors that SDH loss is accompanied by global hypermethylation of histones and DNA, and the constitutive activation of hypoxic signaling. To date, however, there is no clear mechanistic explanation for how succinate-induced activation of hypoxic signaling and global methylation of histones and DNA drives PGL tumorigenesis. Additionally, there is no explanation for why SDH loss has a predilection to specifically cause neuroendocrine tumors. A long-term goal of this proposal is to understand how succinate accumulation promotes tumorigenesis by rewriting the epigenome and altering patterns of gene expression. Our central hypothesis is that understanding cellular responses to succinate accumulation will identify and validate biological targets driving tumorigenesis and susceptible to therapeutic intervention in PGL. Recent work from our laboratory has revealed that the hypoxic and epigenetic effects of succinate accumulation are modulated by oxygen availability. In this project, we seek to understand how succinate accumulation and low oxygen synergize to drive PGL tumorigenesis, and then to identify vulnerabilities intrinsic to SDH-deficient cells.
Aim 1 will characterize the transcriptome- and epigenome-wide effects of succinate accumulation in cell culture models or SDH loss.
Aim 2 will characterize the tissue-specific transcriptome-wide effects of SDH loss in various mouse tissues. Finally, Aim 3 will identify gene products whose loss is synthetically lethal to SDHC-deficient cells.
Paraganglioma (PGL) is a rare and frequently aggressive neuroendocrine tumor that is caused by deranged cellular metabolism. This research aims to 1) understand how deranged metabolism can cause tumorigenesis and 2) identify vulnerabilities of metabolically deranged cells that may be amenable to therapeutic intervention. The results of these studies will guide future strategies to treat this tumor.
| Smestad, John; Erber, Luke; Chen, Yue et al. (2018) Chromatin Succinylation Correlates with Active Gene Expression and Is Perturbed by Defective TCA Cycle Metabolism. iScience 2:63-75 |
| Smestad, John; Hamidi, Oksana; Wang, Lin et al. (2018) Characterization and metabolic synthetic lethal testing in a new model of SDH-loss familial pheochromocytoma and paraganglioma. Oncotarget 9:6109-6127 |
| Hamidi, Oksana; Young Jr, William F; Gruber, Lucinda et al. (2017) Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: A systematic review and meta-analysis. Clin Endocrinol (Oxf) 87:440-450 |
