Division of Nutriomics and Oncology, RCAST, The University of Tokyo, Tokyo, Japan.
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
EMBO J. 2023 Nov 15;42(22):e114032. doi: 10.15252/embj.2023114032. Epub 2023 Oct 2.
Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner. Notably, hypoxia-induced SREBP2 activation was only observed in an immature lineage of bone marrow-derived cells. Single-cell RNA-seq analysis revealed that SREBP2-mediated cholesterol biosynthesis was upregulated in HSCs and monocytes but not in macrophages in the hypoxic bone marrow niche. Moreover, inhibition of cholesterol biosynthesis impaired tumor growth through suppression of pro-tumorigenic immunity and angiogenesis. Thus, our findings indicate that Golgi-ER fusion regulates SREBP2-mediated metabolic alteration in lineage-specific BMDCs under hypoxia for tumor progression.
骨髓来源的细胞（BMDCs）在血管前期浸润缺氧肿瘤，并分化为成熟的巨噬细胞，从而诱导促肿瘤免疫。调节这种分化的一个关键因素是 SREBP2 的激活 - 一种参与肿瘤发生进展的众所周知的转录因子 - 通过未知的细胞机制。在这里，我们表明，缺氧诱导单核细胞来源的髓样细胞中的高尔基解体和高尔基-内质网融合导致 SREBP2 的核易位和激活，而不依赖于 SCAP。值得注意的是，缺氧诱导的 SREBP2 激活仅在骨髓来源细胞的不成熟谱系中观察到。单细胞 RNA-seq 分析表明，SREBP2 介导的胆固醇生物合成在低氧骨髓龛中的 HSCs 和单核细胞中上调，但在巨噬细胞中没有上调。此外，胆固醇生物合成的抑制通过抑制促肿瘤免疫和血管生成来损害肿瘤生长。因此，我们的研究结果表明，在缺氧条件下，高尔基-内质网融合调节谱系特异性 BMDCs 中 SREBP2 介导的代谢改变，以促进肿瘤进展。
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