AXL-initiated paracrine activation of pSTAT3 enhances mesenchymal and vasculogenic supportive features of tumor-associated macrophages
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
Affiliations
Chia-Nung Hung
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Meizhen Chen
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Daniel T. DeArmond
Department of Cardiothoracic Surgery, University of Texas Health Science Center, San Antonio, TX, USA
Cheryl H.-L. Chiu
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Catherine A. Limboy
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Xi Tan
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Meena Kusi
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Chih-Wei Chou
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Li-Ling Lin
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Zhao Zhang
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Chiou-Miin Wang
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Chun-Liang Chen
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA; Office of Nursing Research & Scholarship, School of Nursing, University of Texas Health Science Center, San Antonio, TX, USA
Kohzoh Mitsuya
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Pawel A. Osmulski
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Maria E. Gaczynska
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Nameer B. Kirma
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Ratna K. Vadlamudi
Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, USA; Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX, USA
Don L. Gibbons
Department of Thoracic, Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Steve Warner
Sumitomo Pharma Oncology, Inc, Lehi, UT, USA
Andrew J. Brenner
Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, USA; Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Daruka Mahadevan
Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, USA; Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA
Joel E. Michalek
Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX, USA
Tim H.-M. Huang
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA; Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, USA; Corresponding author
Josephine A. Taverna
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA; Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, USA; Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA; Corresponding author
Summary: 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.
