Abstract 6219: Type V collagen promotes lung adenocarcinoma metastasis by regulating tumor mechanical stress and the implication for prognosis and therapeutic strategies

Abstract Introduction: The mechanical environment of the human body influences physiological and pathological processes, and understanding these biomechanical aspects holds promise for medical research. Tumor microenvironment changes, including extracellular matrix (ECM) alterations, result the changing of mechanical characteristics of the tissue, play a crucial role in cancer progression and metastasis, including lung adenocarcinoma (LUAD), one of a major histology type of lung cancer. This study focuses on elucidating how mechanical characteristics, especially those related to the ECM, influence LUAD and the signaling pathways involved. Methods: Cell culture, transfection, Western blot, immunofluorescence, immunohistochemistry, Transwell assay, scratch wound-healing assay were used to investigate the behavior changes of LUAD cells under different treatment. Bioinformatics analyses, and machine learning-based integrative approaches were employed to build the SVMScore, which was built with relevant base membrane (BM) genes. Patient-derived tumor organoids, myofibroblasts, and co-culture systems were established. Sorafenib, which can inhibited collagen and fibronectin synthesis, was used to explore the proliferation and migration changing of lung cancer cells co-cultured with myofibroblasts. Results: Mechanical stress, simulated by matrix application, enhanced LUAD cell migration and invasion, correlating with ECM alterations and EMT pathway activation. SVMScore predicted LUAD patient prognosis and EMT propensity across multiple datasets, revealing its robust prognostic capabilities. Lower SVMScores were associated with worse survival outcomes, increased cancer-related pathways, higher Tumor Mutation Burden and altered immune microenvironment characteristics. SVMScore was also linked to myofibroblast-secreted COL5A1, a key marker for mechanical stress. Patient tissues with low SVMScores exhibited higher COL5A1 expression, enhanced EMT propensity, and increased internal mechanical stress. Sorafenib, by inhibiting COL5A1 secretion, attenuated the pro-tumor effects of myofibroblasts, inhibiting proliferation and migration of LUAD cells, and rendering LUAD cells more sensitive to chemotherapy. Conclusion: This comprehensive study unveils the intricate relationship between mechanical stress, ECM alterations, and LUAD progression. SVMScore emerges as a potent prognostic tool, reflects tumor mechanical characteristics. Sorafenib intervention targeting COL5A1 secretion provides a potential therapeutic strategy to mitigate LUAD aggressiveness. These findings contribute to a deeper understanding of the biomechanical aspects of LUAD, offering insights for future research and clinical applications. Citation Format: Guangsheng Zhu, Yanan Wang, Yingjie Wang, Chen, Yongwen Li, Hongyu Liu, Jun Chen. Type V collagen promotes lung adenocarcinoma metastasis by regulating tumor mechanical stress and the implication for prognosis and therapeutic strategies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6219.