AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages.

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. [Display omitted] • Concordant AXL-STAT3 enhances M2-like polarization and phenotypic diversity of TAMs • AXL-dependent IL-11 secretion by lung cancer cells and fibroblasts activates STAT3 in TAMs • TAMs promote vasculogenic network via IL-11/AXL-STAT3 manner to upregulate CD44 expression • AXL-STAT3 targeting attenuates M2 polarization and recruitment of TAMs in a mouse model Hung et al. discuss that advanced lung adenocarcinoma (LAC) tumors harbor M2-polarized TAMs with concordant AXL-STAT3 signaling. LAC cells and fibroblasts secrete IL-11 in an AXL-dependent manner. Thus, IL-11 binds to GP130 complex and triggers pSTAT3 activation in M2-polarized macrophages. AXL-STAT3 targeting disrupts intercellular communication and suppresses tumor growth. [ABSTRACT FROM AUTHOR]