Abstract LBA025: AXL-STAT3 targeting of lung tumor microenvironments

Abstract

Abstract The tumor microenvironment contains multiple cell types, each providing a unique functionality in support of malignant growth. To prepare a pro-metastatic niche, a tight signaling network may be present to coordinate delivery of co-stimulatory signals among different cell subpopulations. Here, we report that AXL signaling collaborates with STAT3 to create a symbiotic ecosystem that favors partial epithelial-mesenchymal transition of cancer cells, pro-tumorigenic remodeling of fibroblasts, and M2 polarization of macrophages. To facilitate intercellular communication, AXL-regulated IL-11 secreted from cancer cells and fibroblasts binds to surface GP130 on macrophages to activate STAT3 signaling for M2 polarization. Disruption of AXL-STAT3 circuit not only compromises this signaling co-dependency in lung cancer cells implanted in xenograft mice, but also limits their ability to conscript murine fibroblasts, macrophages, and other immune cells to form a shared habitat for tumor growth and invasion. Therefore, targeting AXL-STAT3 network is an attractive strategy to render inoperative tumor microenvironments that exploit this cellular synchronicity for tumor progression. Significance: Combined targeting of AXL and STAT3 signaling that facilitates co-dependency between malignant and non-malignant cells in tumor microenvironments is a promising strategy for the treatment of advanced lung adenocarcinomas. Citation Format: Josephine A. Taverna. AXL-STAT3 targeting of lung tumor microenvironments [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA025.