Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel.
Cancer Cell. 2021 Jun 14;39(6):779-792.e11. doi: 10.1016/j.ccell.2021.05.002. Epub 2021 Jun 3.
The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.
胶质母细胞瘤的间质亚型被认为是由癌细胞内在改变和外在细胞相互作用共同决定的，但目前仍知之甚少。在这里，我们通过对人类肿瘤和模型系统的单细胞 RNA 测序分析，结合功能实验，剖析了胶质母细胞瘤与微环境的相互作用。我们证明了巨噬细胞诱导胶质母细胞瘤细胞向间充质样（MES 样）状态转变。这种效应在体外和体内都是由巨噬细胞衍生的肿瘤坏死因子-α（OSM）介导的，它与胶质母细胞瘤细胞上的 GP130 与受体（OSMR 或 LIFR）形成复合物，并激活 STAT3。我们表明，MES 样胶质母细胞瘤状态也与巨噬细胞中间充质程序的表达增加以及 T 细胞的细胞毒性增加有关，这突出了免疫微环境的广泛改变，具有潜在的治疗意义。
