AXL-Initiated Paracrine Activation of pSTAT3 Enhances Mesenchymal and Vasculogenic Supportive Features of Tumor-Associated Macrophages

Authors

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

Publication Date

9-26-2023

Journal

Cell Reports

Abstract

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.

Keywords

Humans, Animals, Mice, Tumor-Associated Macrophages, Endothelial Cells, Signal Transduction, Cell Differentiation, Lung Neoplasms, Tumor Microenvironment, Cell Line, Tumor

Comments

Supplementary Materials

PMID: 37659081