AXL通过副分泌方式激活pSTAT3，增强了与肿瘤相关的巨噬细胞的间质和血管生成支持特性。
AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages.
发表日期：2023 Sep 01
作者：
Chia-Nung Hung, Meizhen Chen, Daniel T DeArmond, Cheryl H-L Chiu, Catherine A Limboy, Xi Tan, Meena Kusi, Chih-Wei Chou, Li-Ling Lin, Zhao Zhang, Chiou-Miin Wang, Chun-Liang Chen, Kohzoh Mitsuya, Pawel A Osmulski, Maria E Gaczynska, Nameer B Kirma, Ratna K Vadlamudi, Don L Gibbons, Steve Warner, Andrew J Brenner, Daruka Mahadevan, Joel E Michalek, Tim H-M Huang, Josephine A Taverna
来源：
Cell Reports
摘要：
肿瘤相关巨噬细胞（TAMs）对复杂肿瘤微环境（TMEs）的发展至关重要，并可以在外界信号的刺激下执行不同的细胞程序。然而，支撑这种表型可塑性的上游信号机制尚待阐明。在本研究中，我们报道了TAMs中一致的AXL-STAT3信号被肺癌细胞或癌相关成纤维细胞在细胞因子环境中触发。这种旁分泌作用使TAMs向肿瘤促进的“M2样”表型分化，CD163和潜在的间充质标记物的上调，有助于TAMs的异质性和不同的细胞功能。在这些上调的标记物中，AXL-IL-11-pSTAT3信号级联介导的CD44，增强了巨噬细胞与内皮细胞的相互作用能力，并促进了原始血管网络的形成。我们还发现，AXL-STAT3的抑制可以阻碍在异种移植小鼠模型中TAMs的招募，从而抑制肿瘤生长。这些研究结果表明，AXL-STAT3相关标记物可能应用于定量评估肺癌转移潜力并指导治疗策略。版权所有© 2023作者。由Elsevier Inc.出版。保留所有权利。
Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting "M2-like" phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.