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Dr Tammie Bishop’s and Professor Sir Peter Ratcliffe’s groups shed light on the developmental origins of inherited cancers with mutations in the HIF pathway.

The body’s response to low oxygen (hypoxia) is mediated by hypoxia-inducible factor (HIF), a master transcription factor controlling the expression of hundreds of genes. HIF is also commonly activated in cancer and has attracted widespread interest as a possible therapeutic target. Of note, the HIF-2alpha inhibitor Belzutifan has recently (August 2021) received FDA approval for the treatment of renal cancers in patients with VHL disease, an inherited cancer syndrome resulting in the continuous activation of HIF in the absence of hypoxia and the development of tumours in the kidney and other tissues such as the adrenal medulla (a small organ next to the kidney).

Despite this, genetic mutations of HIF pathway components are rare in most forms of tumours. An exception is tumours of the autonomic paraganglia (the adrenal medulla and extra-adrenal paraganglia including the carotid body), collectively known as pheochromocytomas and paragangliomas (PPGLs). Although these are rare (with an incidence of ~8 per million), they have the interesting feature that almost half of these tumours contain germline mutations, making them one of the most heritable tumours known. Mutations in the HIF pathway that result in the activation of HIF (termed ‘pseudohypoxia’) are particularly common in PPGLs. This has led to the suggestion that HIF activation is driving transformation to cancer, at least in these tumours.

Luise Eckardt and Maria Prange-Barczynska from Dr Tammie Bishop’s and Professor Sir Peter Ratcliffe’s laboratories set out to better understand the role of genetic activation of the HIF pathway in these cancers. The team created a mouse model in which the negative regulator of HIF, called PHD2, is genetically inactivated in a tissue-restricted manner to activate the HIF pathway within the autonomic paraganglia. They studied a particular type of cell called chromaffin cells, from which PPGLs arise.

The researchers describe two populations of chromaffin cells in the adrenal medulla: a dominant mature population of cells and a minority population of immature cells. PHD2 inactivation results in a shift in cell populations towards an immature cell type. In line with this, in the blood of these mice they observe a change in the relative levels of neurotransmitters called catecholamines (such as adrenaline and dopamine) that are produced by chromaffin cells. This catecholamine shift resembles the clinical presentation of patients with pseudohypoxic PPGLs. These effects could be overcome by simultaneous inactivation of PHD2 and HIF-2alpha (but not HIF-1alpha). Further, inactivation of PHD2 in the adult mice did not result in these abnormalities.

Taken together, this work, which is published in the journal Endocrine-Related Cancer, suggests that inactivation of PHD2/activation of HIF-2 results in a shift towards an immature population of chromaffin cells during development to pre-dispose to subsequent PPGL formation and that this underlies the heritability of these tumours. This work has implications for clinical strategies to prevent or treat these rare cancers and suggests that treatment with the clinically licensed HIF-2alpha inhibitor Belzutifan should be targeted to early developmental stages before adulthood.



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