HIF2alpha-Associated Pseudohypoxia Promotes Radioresistance in Pheochromocytoma: Insights from 3D Models

Simple Summary Low oxygen levels (hypoxia) as well as genetic defects activating hypoxia signaling pathways (pseudohypoxia) are known to contribute to tumorigenesis and therapy resistance in various cancers. The genetic background of pheochromocytomas and paragangliomas is well characterized and indicates that pseudohypoxia plays a role in tumor formation and metastatic spread in a subgroup of these tumors. It is, however, unknown how pseudohypoxia affects susceptibility to radiation treatments, which is of particular interest, since targeted radionuclide therapy is one of the few options used against metastatic pheochromocytomas and paragangliomas. To date, no curative treatment is available for metastatic disease. Here, we report on the radioprotective effects of pseudohypoxia against both external irradiation and beta particle-emitting lutetium-177 in a pheochromocytoma tumor spheroid model expressing hypoxia-inducible factor 2 alpha. Our findings highlight hypoxia signaling pathways as potential targets for neo-adjuvant-in particular, radiosensitizing-therapies in pseudohypoxic pheochromocytomas and paragangliomas. Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare neuroendocrine tumors arising from chromaffin tissue located in the adrenal or ganglia of the sympathetic or parasympathetic nervous system. The treatment of non-resectable or metastatic PCCs/PGLs is still limited to palliative measures, including somatostatin type 2 receptor radionuclide therapy with [Lu-177]Lu-DOTA-TATE as one of the most effective approaches to date. Nevertheless, the metabolic and molecular determinants of radiation response in PCCs/PGLs have not yet been characterized. This study investigates the effects of hypoxia-inducible factor 2 alpha (HIF2 alpha) on the susceptibility of PCCs/PGLs to radiation treatments using spheroids grown from genetically engineered mouse pheochromocytoma (MPC) cells. The expression of Hif2 alpha was associated with the significantly increased resistance of MPC spheroids to external X-ray irradiation and exposure to beta particle-emitting [Lu-177]LuCl3 compared to Hif2 alpha-deficient controls. Exposure to [Lu-177]LuCl3 provided an increased long-term control of MPC spheroids compared to single-dose external X-ray irradiation. This study provides the first experimental evidence that HIF2 alpha-associated pseudohypoxia contributes to a radioresistant phenotype of PCCs/PGLs. Furthermore, the external irradiation and [Lu-177]LuCl3 exposure of MPC spheroids provide surrogate models for radiation treatments to further investigate the metabolic and molecular determinants of radiation responses in PCCs/PGLs and evaluate the effects of neo-adjuvant-in particular, radiosensitizing-treatments in combination with targeted radionuclide therapies.

Automated summary

Low oxygen levels and genetic defects activating hypoxia signaling pathways contribute to tumorigenesis and therapy resistance. Pseudohypoxia plays a role in tumor formation and metastasis in pheochromocytomas and paragangliomas. Pseudohypoxia may protect against radiation treatments in these tumors, highlighting potential targets for radiosensitizing therapies.