Effective targeting of cancer stem cells (CSCs) requires neutralization of self-renewal and chemoresistance, but these phenotypes are often regulated by distinct molecular mechanisms. Here we report the ability to target both of these phenotypes via CD55, an intrinsic cell surface complement inhibitor, which was identified in a comparative analysis between CSCs and non-CSCs in endometrioid cancer models. In this context, CD55 functions in a complement-independent manner and required lipid raft localization for CSC maintenance and cisplatin resistance. CD55 regulated self-renewal and core pluripotency genes via ROR2/JNK signaling and in parallel cisplatin resistance via lymphocyte-specific protein tyrosine kinase (LCK) signaling, which induced DNA repair genes. Targeting LCK signaling via saracatinib, an inhibitor currently undergoing clinical evaluation, sensitized chemoresistant cells to cisplatin. Collectively, our findings identify CD55 as a unique signaling node that drives self-renewal and therapeutic resistance through a bifurcating signaling axis and provides an opportunity to target both signaling pathways in endometrioid tumors.

有效靶向癌症干细胞（CSC）需要中和自我更新和化学抗药性，但这些表型通常受独特的分子机制调控。在这里，我们报告了通过CD55（一种固有的细胞表面补体抑制剂）靶向这两种表型的能力，这是在子宫内膜样癌模型中CSC和非CSC之间的比较分析中确定的。在这种情况下，CD55以补体非依赖性的方式起作用，并且需要脂筏定位来维持CSC和顺铂耐药性。CD55通过ROR2 / JNK信号传导调控自我更新和核心多能性基因，并通过淋巴细胞特异性蛋白酪氨酸激酶（LCK）信号传导调控顺铂耐药，从而诱导DNA修复基因。通过saracatinib靶向LCK信号传导，目前正在接受临床评估的一种抑制剂，可使化学耐药细胞对顺铂敏感。总的来说，我们的发现将CD55识别为独特的信号传导节点，该信号通过分叉的信号传导轴驱动自我更新和治疗抗性，并提供了靶向子宫内膜样肿瘤中这两个信号传导途径的机会。