Preprint
Tenascin-C in the early lung cancer tumor microenvironment promotes progression through integrin αvβ1 and FAK
bioRxiv
Cold Spring Harbor Laboratory
09/21/2024
DOI: 10.1101/2024.09.17.613509
PMCID: PMC11429853
PMID: 39345541
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.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.
Details
- Title: Subtitle
- Tenascin-C in the early lung cancer tumor microenvironment promotes progression through integrin αvβ1 and FAK
- Creators
- Shiela C Samson - University of UtahAnthony Rojas - University of UtahRebecca G Zitnay - University of UtahKeith R Carney - University of UtahWakeiyo Hettinga - University of UtahMary C Schaelling - University of UtahDelphine Sicard - Mayo ClinicWei Zhang - University of UtahMelissa Gilbert-Ross - Emory UniversityGrace K Dy - Roswell Park Comprehensive Cancer CenterMichael J Cavnar - University of KentuckyMuhammad Furqan - University of IowaRobert F Browning - Walter Reed National Military Medical CenterAbdul R Naqash - University of Oklahoma Health Sciences CenterBryan P Schneider - Indiana University School of MedicineAhmad Tarhini - Moffitt Cancer CenterDaniel J Tschumperlin - Mayo ClinicAlessandro Venosa - University of UtahAdam I Marcus - Emory UniversityLyska L Emerson - University of UtahBenjamin T Spike - University of UtahBeatrice S Knudsen - University of UtahMichelle C Mendoza - University of Utah
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- DOI
- 10.1101/2024.09.17.613509
- PMID
- 39345541
- PMCID
- PMC11429853
- NLM abbreviation
- bioRxiv
- ISSN
- 2692-8205
- eISSN
- 2692-8205
- Publisher
- Cold Spring Harbor Laboratory
- Language
- English
- Date posted
- 09/21/2024
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984721248802771
Metrics
4 Record Views