Developmental origins of inherited cancers bearing mutations in the oxygen-sensing pathway

The body’s response to low oxygen (hypoxia) is mediated by a master transcription factor known as HIF that controls the expression of hundreds of genes and is often activated in cancer, attracting widespread interest as a therapeutic target. Mutations to HIF pathway components themselves are generally uncommon. But they do occur with some frequency in rare tumors of the autonomic paraganglia, collectively known as pheochromocytomas and paragangliomas (PPGLs). Half of these tumors contain germline mutations—making them among the most heritable of cancers—and mutations that result in the activation of HIF are particularly common in PPGLs.

Luise Eckardt and Maria Prange-Barczynska from the laboratories of Tammie Bishop  and Sir Peter Ratcliffe explored the genetic activation of the HIF pathway in these cancers. They and their colleagues 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. The researchers focused on chromaffin cells, from which PPGLs arise.

PHD2 inactivation results in a shift in chromaffin cell populations towards an immature cell type. These effects could be overcome by simultaneous inactivation of PHD2 and HIF-2α. Further, inactivation of PHD2 in the adult mice did not result in these abnormalities. This work, published in Endocrine-Related Cancer, suggests that activation of HIF-2 results in a shift towards an immature population of chromaffin cells during development to promote PPGL, 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 a recently clinically licensed HIF-2α inhibitor Belzutifan should be targeted to early developmental stages, before adulthood.


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