Wnt3-mediated fibrosis and carcinogenesis of lung squamous cell carcinoma in idiopathic pulmonary fibrosis.
Matsuoka Atsushi, Shien Kazuhiko, Tomida Shuta, Ohki Masayoshi, Torigoe Hidejiro, Hisamatsu Kazuya, Fujiwara Ryota, Ishimura Kosei, Mori Shunsuke, Fujii Ryunosuke, Mimata Asuka, Okada Kazuhiro, Yoshichika Ryo, Yoshikawa Mao, Fukumoto Yuma, Yamamoto Haruchika, Nakajima Kumi, Tanaka Shin, Suzawa Ken, Miyoshi Kentaroh, Okazaki Mikio, Sugimoto Seiichiro, Inoue Hirofumi, Ennishi Daisuke, Toyooka Shinichi
Abstract
Idiopathic pulmonary fibrosis (IPF) increases the risk of lung squamous cell carcinoma (LUSC), yet its molecular pathogenesis remains unclear. We conducted multi-omics analysis, including single-cell RNA sequencing and digital spatial profiling, on LUSC specimens from seven patients with usual interstitial pneumonia (UIP). In UIP lung tissue, metaplastic basal cells arising from the transdifferentiation of alveolar type 2 (AT2) cells were increased. LUSC tumors arising within UIP exhibited molecular profiles and trajectory dynamics suggesting derivation from these metaplastic basal cells. Both UIP-affected tissue and associated tumors showed activation of Wnt signaling, particularly WNT3 expression. Additionally, enrichment of the nuclear factor erythroid 2-related factor 2 (NRF2)-linked antioxidant response was observed in LUSC within UIP. Targeting Wnt/β-catenin signaling restored the sensitivity of these stress-adapted cancer cell lines to oxidative damage. These findings suggest that LUSC within UIP originates from AT2-derived metaplastic basal cells and involves aberrant Wnt3 activation, linking fibrosis to carcinogenesis and highlighting a potential therapeutic strategy.
Key Findings
- Lung squamous cell carcinoma (LUSC) arising in idiopathic pulmonary fibrosis (IPF) originates from alveolar type 2 (AT2) cell-derived metaplastic basal cells.
- Both UIP-affected tissue and associated LUSC tumors show activation of Wnt signaling, particularly WNT3 expression.
- NRF2-linked antioxidant response is enriched in LUSC within UIP, and targeting Wnt/β-catenin signaling restores sensitivity to oxidative damage in cancer cell lines.
Clinical Significance
The study highlights the role of aberrant Wnt3 activation and NRF2-mediated antioxidant responses in linking fibrosis to lung cancer, suggesting that targeting Wnt/β-catenin signaling could be a potential therapeutic strategy for LUSC in IPF patients.
Citation
Matsuoka Atsushi, Shien Kazuhiko, Tomida Shutaet al.. Wnt3-mediated fibrosis and carcinogenesis of lung squamous cell carcinoma in idiopathic pulmonary fibrosis. iScience. 2026-May-15.