Tenascin-C in the early lung cancer tumor microenvironment promotes progression through integrin αvβ1 and FAK
Year: 2024
Type: preprint
Abstract: Pre-cancerous lung lesions are commonly initiated by activating mutations in the RAS pathway, but do not transition to lung adenocarcinomas (LUAD) without additional oncogenic signals. Here, we show that expression of the extracellular matrix protein Tenascin-C (TNC) is increased in and promotes the earliest stages of LUAD development in oncogenic KRAS-driven lung cancer mouse models and in human LUAD. TNC is initially expressed by fibroblasts and its expression extends to tumor cells as the tumor becomes invasive. Genetic deletion of TNC in the mouse models reduces early tumor burden and high-grade pathology and diminishes tumor cell proliferation, invasion, and focal adhesion kinase (FAK) activity. TNC stimulates cultured LUAD tumor cell proliferation and migration through engagement of αv-containing integrins and subsequent FAK activation. Intringuingly, lung injury causes sustained TNC accumulation in mouse lungs, suggesting injury can induce additional TNC signaling for early tumor cell transition to invasive LUAD. Biospecimens from patients with stage I/II LUAD show TNC in regions of FAK activation and an association of TNC with tumor recurrence after primary tumor resection. These results suggest that exogenous insults that elevate TNC in the lung parenchyma interact with tumor-initiating mutations to drive early LUAD progression and local recurrence.
Authors: Shiela C. Samson, Anthony Rojas, Rebecca G. Zitnay, Keith R. Carney, Wakeiyo Hettinga, Mary C. Schaelling, Delphine Sicard, Wei Zhang, Melissa Gilbert-Ross, Grace K. Dy, Michael J. Cavnar, Muhammad Furqan, Robert F. Browning, Abdul R. Naqash, Bryan P. Schneider, Ahmad Tarhini, Daniel J. Tschumperlin, Alessandro Venosa, Adam I. Marcus, Lyska L. Emerson, Benjamin T. Spike, Beatrice S. Knudsen, Michelle C. Mendoza
Institutions: University of Utah, Huntsman Cancer Institute, Mayo Clinic, Emory University, Winship Cancer Institute, Roswell Park Comprehensive Cancer Center, University of Kentucky, University of Iowa Health Care, Walter Reed National Military Medical Center, OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Indiana University Indianapolis, Indiana University School of Medicine, Moffitt Cancer Center, Long Island University
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4402707407