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

Cell Reports (Sep 2023)

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

Journal volume & issue: Vol. 42, no. 9
p. 113067

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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