Researchers at Karolinska Institutet and Umeå University have investigated how the protein HIF2α affects neuroblastoma, a severe form of childhood cancer. The results show that high levels of HIF2α can reduce the growth of tumor cells and promote their maturation into a less aggressive cell type.
Neuroblastoma is a type of cancer that affects the sympathetic nervous system in young children and is often difficult to treat, especially when the tumor cells carry multiple copies of the MYCN gene. In the new study, researchers focused on HIF2α, a protein previously thought to promote cancer development.
When the researchers increased the amount of HIF2α in neuroblastoma cells with many copies of the MYCN gene, they observed a significant reduction in MYCN protein levels. At the same time, the expression of genes typical of noradrenergic cells in the adrenal medulla increased, suggesting that the tumor cells began to resemble more mature chromaffin cells. The cells also stopped dividing as rapidly and developed long extensions, a sign of ongoing maturation.
In mouse models of neuroblastoma, tumor growth was clearly reduced upon induction of high levels of HIF2α . Analysis of patient samples from children with neuroblastoma showed that high levels of EPAS1 (the gene encoding HIF2α) were associated with low levels of MYCN and with genes typical of noradrenergic cells. Moreover, patients with high EPAS1 levels generally had a better prognosis.
"Our results show that high levels of HIF2α lead to decreased MYCN levels, reduced cell proliferation, and a shift toward a more mature cell type," says Juan Yuan , one of the researchers behind the study at the Department of Cell and Molecular Biology (CMB).
The study thus challenges the previous notion that HIF2α always acts as a cancer driver in neuroblastoma. Instead, the findings suggest that the protein may, in some cases, play a tumor suppressive and maturation-promoting role.
"This gives us new insights into how neuroblastoma develops and may eventually contribute to new treatment strategies," says Johan Holmberg , professor at the Department of Molecular Biology at Umeå University and affiliated to CMB at KI.
Publication
The study, which is supported by the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Kempe Foundation and the Faculty of Medicine's Strategic Research Resource at Umeå University, is published in the scientific journal PNAS.
Yuan J, Maitra S, Antoniou E, Zhu J, Li W, Demirel IS, Toskas K, Martinez IL, Ozcimen L, Lindehell H, Muhr J, Stenman J, Kogner P, Bedoya-Reina OC, Schlisio S, Holmberg J
Proc Natl Acad Sci U S A 2025 Oct;122(43):e2516922122
