We describe a unique patient-derived xenograft (PDX) and cell culture model of
succinate dehydrogenase-deficient
gastrointestinal stromal tumor (SDH-deficient GIST), a rare mesenchymal
tumor that can occur in association with
paragangliomas in hereditary and non-hereditary syndromes. This model is potentially important for what it might reveal specifically pertinent to this rare
tumor type and, more broadly, to other types of SDH-deficient
tumors. The primary
tumor and xenografts show a very high proliferative fraction, and distinctive morphology characterized by tiny cells with marked autophagic activity. It is likely that these characteristics resulted from the combination of the germline SDHB mutation and a somatic KRAS G12D mutation. The most broadly relevant findings to date concern
oxygen and oxidative stress. In
paragangliomas harboring SDHx mutations, both hypoxic signaling and oxidative stress are putative drivers of
tumor growth. However, there are no models for SDH-deficient
paragangliomas. This related model is the first from a SDHB-mutated human
tumor that can be experimentally manipulated to study mechanisms of
oxygen effects and novel treatment strategies. Our data suggest that
tumor growth and survival require a balance between protective effects of hypoxic signaling vs deleterious effects of oxidative stress. While reduced
oxygen concentration promotes
tumor cell survival, a further survival benefit is achieved with
antioxidants. This suggests potential use of drugs that increase oxidative stress as novel
therapies. In addition, autophagy, which has not been reported as a major finding in any type of SDH-deficient
tumor, is a potential target of agents that might trigger autophagic cell death.