Tumor-associated collagen signature in relation to metastasis in lung adenocarcinoma

Background: In lung adenocarcinoma (LUAD), a subset of tumors metastasizes to lymph nodes while others do not, despite having a similar tumor stage (T stage). The tumor extracellular matrix (ECM), particularly collagen and elastin, may play a critical role in this variability. This study aimed to determine whether differences in collagen architecture and elastin content within the tumor ECM are associated with susceptibility to nodal metastasis in LUAD. Methods: LUAD tissue samples were obtained from 120 patients (54 metastatic and 66 non-metastatic) diagnosed between 2005 and 2022 at Roswell Park Comprehensive Cancer Center. Sections were stained with Masson's trichrome and Elastica Van Gieson on separate slide replicates. Collagen and elastin volume fractions were quantified using Aperio ImageScope. Collagen fiber alignment was assessed using second harmonic generation (SHG) imaging and analyzed with CurveAlign software. Results: Metastatic tumors demonstrated significantly higher unidirectional alignment of collagen fibers compared to the crisscross pattern seen in non-metastatic tumors (0.87 vs. 0.78, P=0.003). Elastin volume fraction was significantly lower in metastatic tumors (0.29 vs. 0.38, P=0.001), while total collagen content did not differ significantly (P=0.87). The elastin-to-collagen ratio was significantly reduced in metastatic tumors (P=0.002), indicating a shift in ECM composition rather than an absolute increase in collagen. Conclusions: Decreased elastin content and increased collagen fiber alignment are associated with nodal metastasis in LUAD and may reflect alterations in stromal organization and stiffness that promote tumor dissemination. These ECM features may serve as potential biomarkers for identifying LUAD patients at higher risk for nodal metastasis. Further large-scale studies are needed for validation.