Cancer cells have been likened to speeding cars. Mutated oncogenes hold down accelerator pedals;mutated tumor suppressor genes ruin brakes. Though often helpful, this analogy completely fails in the fascinating case of familial paraganglioma (PGL). Amazingly, PGL is a neuroendocrine cancer caused by loss of succinate dehydrogenase in the tricarboxylic acid (TCA) cycle of central metabolism. This is equivalent to severely disabling the engine of a car! How can loss-of-function mutations in a metabolic enzyme possibly be oncogenic, and why only in neuroendocrine cells? These irresistible biochemical questions drive this proposal, and answers will have significance for cancer therapy far beyond PGL. The central hypothesis is that succinate accumulation due to loss of SDH triggers neuroendocrine cell transformation by epigenetic effects resulting from inhibition of at least three different 2-ketoglutarate- dependent dioxygenase enzymes that produce succinate as a byproduct. It is as if the speeding car of cancer loses control because the driver is intoxicated by fumes from a faulty engine! We hypothesize that dioxygenase inhibition alters gene expression by novel epigenetic effects including (i) inappropriate activation of Hypoxia Inducible Factor (HIF), (ii) accumulation of methylated histones, and (iii) depletion of genomic 5-hydroxymethylcytosine. The strategy is to characterize PGL tumors and mammalian cells lacking SDH function, and to develop a nematode model of PGL for drug screening in Caenorhabditis elegans.
Aim 1 will seek evidence for dioxygenase inhibition in primary human PGL tumor samples.
Aim 2 will explore dioxygenase inhibition in cultured human and mouse cells lacking SDH.
Aim 3 will monitor PGL tumorigenesis in mice with conditional SDH disruption. Finally, Aim 4 will develop a C. elegans model of PGL to uncover new therapeutics.
Sometimes rare forms of cancer can teach us about more common cancers. Paraganglioma is a rare cancer that can run in families. Paraganglioma is caused when special nerve cells in the abdomen grow out of control. We know that paragangliomas start because of mistakes in the genes of patients, and we even know what genetic recipes have errors in these patients. We don't understand why these particular errors causes this cancer-in fact, it is completely unexpected because the errors result in a broken protein machine that should make it very difficult for the cancer cells to get energy from blood sugar. Our lab now has evidence for why this metabolic problem causes the tumor cells to grow. We will test this idea using cultured cells, mice, and even nematode worms. Ultimately we will better understand this rare but important cancer.