美国杰克逊实验室Guangwen Ren研究组发现，含脂肺间充质细胞(MCs)通过肿瘤细胞和自然杀伤细胞(NK)的代谢重编程促进乳腺癌转移。这一研究成果发表在2022年12月6日出版的国际学术期刊《细胞—代谢》上。

在乳腺癌模型中，他们发现MCs在转移前阶段积累中性脂质。这部分是由白细胞介素-1β (IL-1β)诱导的缺氧诱导脂滴相关(HILPDA)介导的，后者随后抑制肺MCs中的脂肪甘油三酯脂肪酶(ATGL)活性。小鼠中MC特异性ATGL或HILPDA基因的消融分别增强和减少了乳腺癌的肺转移，这表明含脂MCs具有促进转移的作用。

在机制上，含脂的MCs通过外泌体样囊泡将其脂质运输到肿瘤细胞和NK，导致肿瘤细胞生存和增殖以及NK细胞功能障碍的增强。阻断IL-1β单独有效，可提高NK细胞过继免疫治疗减轻肺转移的疗效。总的来说，肺MCs代谢调节肿瘤细胞和抗肿瘤免疫，促进乳腺癌肺转移。

据介绍，虽然已知远处的器官环境支持原发肿瘤的转移，但其在这一过程中的代谢作用仍未确定。

附：英文原文

Title: Lipid-laden lung mesenchymal cells foster breast cancer metastasis via metabolic reprogramming of tumor cells and natural killer cells

Author: Zheng Gong, Qing Li, Jiayuan Shi, Edison T. Liu, Leonard D. Shultz, Guangwen Ren

Issue&Volume: 2022/12/06

Abstract: While the distant organ environment is known to support metastasis of primary tumors,its metabolic roles in this process remain underdetermined. Here, in breast cancermodels, we found lung-resident mesenchymal cells (MCs) accumulating neutral lipidsat the pre-metastatic stage. This was partially mediated by interleukin-1β (IL-1β)-inducedhypoxia-inducible lipid droplet-associated (HILPDA) that subsequently represses adiposetriglyceride lipase (ATGL) activity in lung MCs. MC-specific ablation of the ATGLor HILPDA genes in mice reinforced and reduced lung metastasis of breast cancer respectively,suggesting a metastasis-promoting effect of lipid-laden MCs. Mechanistically, lipid-ladenMCs transported their lipids to tumor cells and natural killer (NK) cells via exosome-likevesicles, leading to heightened tumor cell survival and proliferation and NK celldysfunction. Blockage of IL-1β, which was effective singly, improved the efficacyof adoptive NK cell immunotherapy in mitigating lung metastasis. Collectively, lungMCs metabolically regulate tumor cells and anti-tumor immunity to facilitate breastcancer lung metastasis.

DOI: 10.1016/j.cmet.2022.11.003

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00494-6