Developmental heterogeneity of embryonic neuroendocrine chromaffin cells and their maturation dynamics

The role of HIF2α, encoded by EPAS1, in neuroblastoma remains controversial. Here we demonstrate that induction of high levels of HIF2α in MYCN-amplified neuroblastoma cells results in a rapid and profound reduction of the oncoprotein MYCN. This is followed by an upregulation of genes characteristic of noradrenergic cells in the adrenal medulla. Additionally, upon induction of HIF2α, the proliferation rate drops substantially, and cells develop elongated neurite-like protrusions, indicative of differentiation. In vivo HIF2α induction in established xenografts significantly attenuates tumour growth. Notably, analysis of sequenced neuroblastoma patient samples, revealed a negative correlation between EPAS1 and MYCN expression and a strong positive correlation between EPAS1 expression, high expression levels of noradrenergic markers, and improved patient outcome. This was paralleled by analysis of human adrenal medulla datasets wherein EPAS1 expression was prominent in populations with high expression levels of genes characteristic of noradrenergic chromaffin cells. Our findings show that high levels of HIF2α in neuroblastoma, leads to drastically reduced MYCN protein levels, cell cycle exit, and noradrenergic cell differentiation. Taken together, our results challenge the dogma that HIF2α acts as an oncogene in neuroblastoma and rather suggest that HIF2α has potential tumour suppressor capacity in this particular disease.

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Hif-2α programs oxygen chemosensitivity in chromaffin cells

Prange-Barczynska,

Jones,

Sugimoto

et al. 2024

Journal of Clinical Investigation

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The study of transcription factors that determine specialised neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neurone-like electrophysiologically excitable cells that link the oxygen concentration of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by Type I cells of the carotid body and recent work has revealed one isoform of the hypoxia-inducible transcription factor (HIF), HIF-2α, to have a non-redundant role in the development and function of that organ. Here we show that activation of HIF-2α, including isolated overexpression of HIF-2α but not HIF-1α, is sufficient to induce oxygen chemosensitivity in adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues resembling the foetal organ of Zuckerkandl that also manifests oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of gene classes that are ordinarily characteristic of the carotid body, including G-protein regulators and atypical subunits of mitochondrial cytochrome oxidase. Overall, the findings suggest that, at least in certain tissues, HIF-2α acts as a phenotypic driver for cells that display oxygen chemosensitivity, thus linking two major oxygen sensing systems.

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Developmental heterogeneity of embryonic neuroendocrine chromaffin cells and their maturation dynamics

Cited by 3 publications

References 60 publications

Hand2 Immunohistochemistry in the Diagnosis of Paragangliomas and Other Neuroendocrine Neoplasms

Hand2 Immunohistochemistry in the Diagnosis of Paragangliomas and Other Neuroendocrine Neoplasms

HIF2α negatively regulates MYCN protein levels and promotes a low-risk noradrenergic phenotype in neuroblastoma

Hif-2α programs oxygen chemosensitivity in chromaffin cells

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