Shedding Phosphorylated Axl Receptor in Lung Adenocarcinoma: Dual-Domain Immunohistochemistry Approach

Axl, a receptor tyrosine kinase, is linked to epithelial-mesenchymal transition (EMT). This study aimed to investigate the biologic implications of extracellular domain shedding of phosphorylated Axl (pAxl) in lung adenocarcinoma, focusing on spread through air spaces (STAS) as a potential pathologic representation of EMT.

This study included 202 patients with resected lung adenocarcinoma. A dual-domain immunohistochemistry approach using separate staining for the extracellular and intracellular domains was used to classify the tumors into shedding and nonshedding pAxl groups. Prognostic analysis was performed using recurrence-free probability (RFP) as the primary outcome. Furthermore, by using a public gene database, we developed the "shedding pAxl score" to experimentally investigate correlations with EMT-related genes.

The shedding pAxl group exhibited significantly worse prognosis than the nonshedding pAxl group (5-year RFP, 54% and 80%, respectively; p < 0.001). This prognostic stratification of pAxl shedding was predominant in STAS-positive patients (5-year RFP, 37% and 75%, p < 0.001), but not in STAS-negative patients (5-year RFP, 73% and 84%, p = 0.3). Multivariate analysis revealed that pathologic stage and pAxl shedding were independent factors for recurrence (hazard ratio 2.28 [1.24-4.91], p = 0.008). The shedding pAxl score correlated strongly with the established EMT signature score (p < 0.001, R = 0.61).

Shedding pAxl has a prognostic impact on lung adenocarcinoma, with a significant effect modification related to STAS. The developed shedding pAxl score, strongly associated with EMT, provides foundational knowledge for further studies on this phenomenon in lung cancer progression.