WCLC 2025 - Posters & ePosters-P2.06.47 Axl Receptor Shedding and EMT in Lung Adenocarcinoma: Prognostic Implications Based on STAS

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This study investigates the role of Axl receptor shedding and epithelial-mesenchymal transition (EMT) in lung adenocarcinoma (LUAD), focusing on prognostic implications related to spread through air spaces (STAS), a known adverse pathological feature. Axl is a receptor tyrosine kinase associated with EMT and tumor progression, which undergoes extracellular domain shedding via metalloproteases ADAM10 and ADAM17. The biological significance and prognostic impact of this "Axl shedding" were previously unclear.<br /><br />The authors hypothesized that Axl shedding represents EMT dynamics influencing STAS formation and patient outcomes. They analyzed a cohort of 202 LUAD patients who underwent lung cancer resection between 2013 and 2017, excluding non-adenocarcinoma histologies, small tumors, and advanced disease stages. Using dual-domain immunohistochemistry and RNA sequencing data, they developed a "shedding pAxl score" reflecting the transcriptomic signature of Axl shedding components and correlated it with established EMT gene expression signatures.<br /><br />Key findings include that patients exhibiting Axl shedding had significantly worse five-year recurrence-free survival (54% vs. 80% for non-shedding), particularly notable in those with STAS (37% vs. 75%). Multivariable analyses confirmed shedding pAxl as an independent prognostic factor in the entire cohort (HR=2.28) and especially among STAS-positive patients (HR=3.06), whereas its impact was not significant in STAS-negative cases. The shedding pAxl score correlated strongly with mesenchymal gene upregulation, supporting its biological relevance as an EMT marker.<br /><br />In conclusion, phosphorylated Axl receptor shedding is a novel, independent biomarker predicting poor prognosis in LUAD, especially in the context of STAS. This study highlights the clinical and biological importance of Axl shedding in EMT-driven tumor aggressiveness, providing insights that could refine risk stratification and potential therapeutic targeting in lung adenocarcinoma. The findings have been accepted for publication in the Journal of Thoracic Oncology Clinical and Research Reports.

Asset Subtitle

Shuji Mishima

Meta Tag

Speaker Shuji Mishima

Topic Pathology and Biomarkers

Keywords

Axl receptor shedding

epithelial-mesenchymal transition

lung adenocarcinoma

spread through air spaces

STAS

prognostic biomarker

ADAM10

ADAM17

shedding pAxl score

tumor aggressiveness