德克萨斯大学安德森癌症中心Ronald A. DePinho研究组取得一项新突破。他们发现巨噬细胞与胶质瘤细胞之间的共生相互作用揭示了PTEN缺失型胶质瘤的合成致死性。 2019年6月10日出版的《Cancer Cell》发表了这项成果。

研究者通过对多形性胶质母细胞瘤（GBM）模型中的胶质瘤细胞的特征与功能进行分析研究，发现PTEN缺乏能够激活YAP1基因，后者直接上调Lysyl氧化酶（LOX）的表达。从分子机制上来说，分泌的LOX是一种巨噬细胞化学吸引剂，能够激活巨噬细胞中的β1整合素-PYK2通路。这些浸润的巨噬细胞分泌出SPP1，从而维持胶质瘤细胞的存活并刺激肿瘤内的血管生成。在PTEN缺失型GBM模型中，抑制LOX的分泌，能够显著抑制巨噬细胞浸润和肿瘤发展。相应地研究发现，在GBM病人中，YAP1-LOX和β1整合素-SPP1s信号与增高巨噬细胞密度及降低生存率呈正相关关系。这种胶质瘤细胞与巨噬细胞的共生相互作用为PTEN缺失型GBM疾病提供了特有的治疗靶点。

研究发现，不同细胞类型间的异型相互作用可促进肿瘤的发展，研究肿瘤细胞与周围环境中细胞间相互关系，可以为扩大肿瘤疾病的治疗干预提供更多的潜在方案。

附：英文原文

Title: Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma

Author: Peiwen Chen, Di Zhao, Jun Li, Xin Liang, Jiexi Li, Andrew Chang, Verlene K. Henry, Zhengdao Lan, Denise J. Spring, Ganesh Rao, Y. Alan Wang, Ronald A. DePinho

Issue&Volume: Jun 10, 2019 Volume 35Issue 6

Abstract: Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the β1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and β1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM.

DOI: https://doi.org/10.1016/j.ccell.2019.05.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30241-7