The iron-sulfur cluster assembly factor FDX2 is required for tumor initiation but not for growth of established tumors in transplantation models

Iron-sulfur (Fe-S) clusters bind to Fe-S proteins and are required for their function and/or structural stability. Recent work reveals an essential role for Fe-S cluster biosynthesis in cancer cell proliferation in vitro, but how Fe-S cluster metabolism contributes to tumor activity in vivo is unclear. Here we report analysis suggesting a stage-specific requirement for FDX2, a critical component of the Fe-S cluster assembly complex, in cancer progression. Using inducible loss-of-function transplant models of a human ovarian cancer line, we show that FDX2 is required for tumor initiation and metastasis but not for growth of established tumors in mice. We report global upregulation of Fe-S proteins under low oxygen conditions and concomitant attenuation of FDX2 loss-mediated disruption of many Fe-S proteins, enabling FDX2-independent proliferation. Our findings highlight a differential requirement of Fe-S cluster biosynthesis for tumor metastasis versus growth and low oxygen-mediated mitigation of Fe-S protein loss promoted by FDX2 deficiency.