Baldavira Camila Machado, Prieto Tabatha Gutierrez, de Souza Maria Luiza Fernezlian, Qualiotto Aline Nery, Velosa Ana Paula Pereira, Teodoro Walcy Rosolia, Takagaki Teresa, Ab'Saber Alexandre, Capelozzi Vera Luiza
Laboratory of Lung Histomorphometry and Genomics, Department of Pathology, Faculty of Medicine, University of São Paulo, Brazil.
Laboratory of Lung Histomorphometry and Genomics, Department of Pathology, Faculty of Medicine, University of São Paulo, Brazil.
Biochim Biophys Acta Mol Basis Dis. 2025 Apr;1871(4):167709. doi: 10.1016/j.bbadis.2025.167709. Epub 2025 Feb 11.
Non-small cell lung carcinoma (NSCLC), comprising adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), is characterized by an active desmoplastic stroma with an accumulation of extracellular matrix (ECM) proteins. ECM remodeling is a key feature of cancer progression, but the identification of specific therapeutic targets within this compartment remains challenging. Recent studies suggest a link between increased desmoplastic stroma and malignancy in NSCLC, the role of ECM proteins in disease pathogenesis remains unclear.
We analyzed an exploratory cohort of Pan-Cancer Atlas and a study cohort to identify differentially expressed ECM proteins. Our focus was on fibrillar components (elastin, fibrillin, collagens), glycosaminoglycans (chondroitin sulfate and heparan sulfate), and matricellular proteins (SPARC). Bioinformatics analysis highlighted matrix proteins that modulate ECM functionality and structure, potentially serving as biomarkers and/or therapeutic targets.
Adenocarcinomas exhibited an ECM enriched with abnormal elastin, chondroitin sulfate, and SPARC. Collagen IV expression in the basement membrane was reduced, while collagen III and V were prominent around tumors. LUSC showed more fibrotic ECM, leading to a stiffer microenvironment. While LUSC's basement membrane may be fragmented, it often retains more intact collagen IV compared to LUAD. High elastin expression in LUAD correlated with smaller tumors (P = 0.022), while fibrillin-2 expression was linked to T1 stage (P = 0.035) and pathological stage I (P = 0.014). In LUSC, elastin expression correlated with negative lymph nodes (P = 0.037). SPARC was an independent factor for overall survival for both subtypes (P < 0.05).
This study provides insights into matrix changes in NSCLC and identifies promising candidates for targeted therapies.
非小细胞肺癌（NSCLC）包括腺癌（LUAD）和鳞状细胞癌（LUSC），其特征是具有活跃的促结缔组织增生性基质，伴有细胞外基质（ECM）蛋白的积累。ECM重塑是癌症进展的关键特征，但在这一区域内确定特定的治疗靶点仍然具有挑战性。最近的研究表明，NSCLC中促结缔组织增生性基质增加与恶性肿瘤之间存在联系，然而ECM蛋白在疾病发病机制中的作用仍不清楚。
我们分析了泛癌图谱的一个探索性队列和一个研究队列，以鉴定差异表达的ECM蛋白。我们重点关注纤维成分（弹性蛋白、原纤蛋白、胶原蛋白）、糖胺聚糖（硫酸软骨素和硫酸乙酰肝素）和基质细胞蛋白（SPARC）。生物信息学分析突出了调节ECM功能和结构的基质蛋白，这些蛋白可能作为生物标志物和/或治疗靶点。
腺癌表现出富含异常弹性蛋白、硫酸软骨素和SPARC的ECM。基底膜中的IV型胶原蛋白表达减少，而III型和V型胶原蛋白在肿瘤周围突出。LUSC表现出更多的纤维化ECM，导致微环境更硬。虽然LUSC的基底膜可能破碎，但与LUAD相比，它通常保留更多完整的IV型胶原蛋白。LUAD中高弹性蛋白表达与较小肿瘤相关（P = 0.022），而原纤蛋白-2表达与T1期（P = 0.035）和病理I期（P = 0.014）相关。在LUSC中，弹性蛋白表达与阴性淋巴结相关（P = 0.037）。SPARC是两种亚型总生存的独立因素（P < 0.05）。
本研究深入了解了NSCLC中的基质变化，并确定了有前景的靶向治疗候选物。
