Tenascin-C in the early lung cancer tumor microenvironment promotes progression through integrin αvβ1 and FAK.

Autor: Samson SC; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.; Huntsman Cancer Institute, Salt Lake City, UT 84112., Rojas A; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.; Huntsman Cancer Institute, Salt Lake City, UT 84112., Zitnay RG; Huntsman Cancer Institute, Salt Lake City, UT 84112.; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112., Carney KR; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.; Huntsman Cancer Institute, Salt Lake City, UT 84112., Hettinga W; Huntsman Cancer Institute, Salt Lake City, UT 84112.; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112., Schaelling MC; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.; Huntsman Cancer Institute, Salt Lake City, UT 84112., Sicard D; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905., Zhang W; Huntsman Cancer Institute, Salt Lake City, UT 84112.; Department of Pathology, University of Utah, Salt Lake City, UT 84112., Gilbert-Ross M; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322., Dy GK; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203., Cavnar MJ; Department of Surgery, University of Kentucky, Lexington, KY 40508., Furqan M; Department of Internal Medicine, University of Iowa Health Care, Iowa City, IA 52246., Browning RF Jr; Department of Medicine, Walter Reed National Military Medical Center, Bethesda, MD 20889., Naqash AR; Division of Medical Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104., Schneider BP; Department of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202., Tarhini A; Departments of Cutaneous Oncology and Immunology, H. Lee Moffit Cancer Center & Research Institute, Tampa, FL 33612., Tschumperlin DJ; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905., Venosa A; Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112., Marcus AI; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322.; Long Island University, College of Veterinary Medicine, Brookville, NY 11548., Emerson LL; Huntsman Cancer Institute, Salt Lake City, UT 84112.; Department of Pathology, University of Utah, Salt Lake City, UT 84112., Spike BT; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.; Huntsman Cancer Institute, Salt Lake City, UT 84112., Knudsen BS; Huntsman Cancer Institute, Salt Lake City, UT 84112.; Department of Pathology, University of Utah, Salt Lake City, UT 84112., Mendoza MC; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112.; Huntsman Cancer Institute, Salt Lake City, UT 84112.; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 21. Date of Electronic Publication: 2024 Sep 21.
DOI: 10.1101/2024.09.17.613509
Abstrakt: 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.
Databáze: MEDLINE