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

doi:10.1016/j.celrep.2023.113067

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

Cell Rep. 2023 Sep 26;42(9):113067. doi: 10.1016/j.celrep.2023.113067. Epub 2023 Sep 1.

Authors

Chia-Nung Hung¹, Meizhen Chen¹, Daniel T DeArmond², Cheryl H-L Chiu¹, Catherine A Limboy¹, Xi Tan¹, Meena Kusi¹, Chih-Wei Chou¹, Li-Ling Lin¹, Zhao Zhang¹, Chiou-Miin Wang¹, Chun-Liang Chen³, Kohzoh Mitsuya¹, Pawel A Osmulski¹, Maria E Gaczynska¹, Nameer B Kirma¹, Ratna K Vadlamudi⁴, Don L Gibbons⁵, Steve Warner⁶, Andrew J Brenner⁷, Daruka Mahadevan⁷, Joel E Michalek⁸, Tim H-M Huang⁹, Josephine A Taverna¹⁰

Affiliations

¹ Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
² Department of Cardiothoracic Surgery, University of Texas Health Science Center, San Antonio, TX, USA.
³ 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.
⁴ 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.
⁵ Department of Thoracic, Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Sumitomo Pharma Oncology, Inc, Lehi, UT, USA.
⁷ 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.
⁸ Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX, USA.
⁹ 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. Electronic address: huangt3@uthscsa.edu.
¹⁰ 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. Electronic address: tavernaj@uthscsa.edu.

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: AXL; CP: Cancer; CP: Immunology; CyTOF; Dubermatinib; Momelotinib; STAT3; tumor microenvironment; tumor-associated macrophage.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Abstract

Publication types

MeSH terms

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