组织驻留巨噬细胞转移硒转运蛋白保护胰腺癌免于铁死亡
Resident tissue macrophages transfer selenium transporter protein to protect pancreatic cancer from ferroptosis
胰腺导管腺癌（PDAC）预后差，其中存在肿瘤发生前就有的组织驻留巨噬细胞和肿瘤发展过程中招募的单核细胞来源巨噬细胞，二者作用此前不清。研究结合单细胞测序、空间分析、谱系追踪、巨噬细胞清除和硒示踪发现，驻留巨噬细胞偏好定位于肿瘤边缘，促进上皮-间质转化（细胞获得侵袭能力的过程）、肿瘤生长和转移。机制上，驻留巨噬细胞通过 LRP8 依赖的摄取，把硒转运蛋白 Selenop 转移给处于上皮-间质转化高状态的肿瘤细胞，增加肿瘤细胞硒供应、限制脂质过氧化，使其免于铁死亡（一种铁依赖的细胞死亡方式）。删除巨噬细胞的 Selenop 或破坏肿瘤细胞的 Lrp8 可减少转化和肿瘤进展，而抑制铁死亡可逆转巨噬细胞清除的效果。人胰腺癌中也见到边缘富集、靠近高转化状态肿瘤细胞的 SEPP1 阳性驻留巨噬细胞，提示存在保守的巨噬细胞来源硒微环境。
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摘要Abstract
Pancreatic ductal adenocarcinoma (PDAC), an aggressive cancer with a poor prognosis, contains resident tissue macrophages (RTMs) present before tumor onset and monocyte-derived macrophages recruited during tumor development, but their distinct roles in supporting tumor progression remain unclear. Combining single-cell profiling, spatial analysis, lineage tracing, RTM depletion, and selenium tracing, we found that RTMs preferentially localize at the tumor border, where they promote epithelial-mesenchymal transition (EMT), tumor growth, and metastasis. Mechanistically, RTMs transfer the selenium transporter Selenop to EMThi tumor cells through LRP8-dependent uptake, increasing tumor-cell selenium availability, limiting lipid peroxidation, and shielding EMThi tumor cells from ferroptosis. RTM-specific Selenop deletion or tumor-cell Lrp8 disruption reduced EMT and tumor progression, whereas ferroptosis inhibition reversed the effect of RTM depletion. Human PDAC showed border-enriched SEPP1+ RTMs near EMThi tumor cells, suggesting a conserved macrophage-derived selenium niche that supports invasive tumor states and highlighting the potential for targeting RTMs or their secretory factors in PDAC.