Iron commensalism of mesenchymal glioblastoma promotes ferroptosis susceptibility upon dopamine treatment

The heterogeneity of glioblastoma multiforme (GBM) leads to poor patient prognosis. Here, we aim to investigate the mechanism through which GBM heterogeneity is coordinated to promote tumor progression. We find that proneural (PN)-GBM stem cells (GSCs) secreted dopamine (DA) and transferrin (TF), inducing the proliferation of mesenchymal (MES)-GSCs and enhancing their susceptibility toward ferroptosis. PN-GSC-derived TF stimulates MES-GSC proliferation in an iron-dependent manner. DA acts in an autocrine on PN-GSC growth in a DA receptor D1-dependent manner, while in a paracrine it induces TF receptor 1 expression in MES-GSCs to assist iron uptake and thus enhance ferroptotic vulnerability. Analysis of public datasets reveals worse prognosis of patients with heterogeneous GBM with high iron uptake than those with other GBM subtypes. Collectively, the findings here provide evidence of commensalism symbiosis that causes MES-GSCs to become iron-addicted, which in turn provides a rationale for targeting ferroptosis to treat resistant MES GBM.