LARC患者通常接受辅助治疗，但隐藏的微转移仍然限制了OS的改善。本研究旨在探讨VASN对直肠癌肺转移的影响，了解其潜在的分子机制，以指导辅助化疗的选择。测序数据来自中山大学肿瘤防治中心（SYSUCC）和公开的直肠癌肺转移患者的测序数据数据经过仔细分析。 VASN 在肺转移中的功能作用在体内和体外得到了验证。进行免疫共沉淀 (co-IP)、免疫荧光和救援实验来揭示 VASN 的潜在分子机制。此外，还检查并分析了肿瘤样本中 VASN 表达水平与肺转移状态、肿瘤分期、辅助化疗获益和生存结果的相关性。我们的研究揭示了 LARC 患者高 VASN 表达与肺转移之间的显着相关性。体外和体内实验表明，VASN可以促进结直肠癌的细胞增殖、转移和耐药性。从机制上讲，VASN 与 NOTCH1 蛋白相互作用，导致 NOTCH 和 MAPK 通路同时激活。临床上，VASN阳性患者和VASN高患者中分别有90%和53.5%的患者出现肺转移和晚期肿瘤分期，VASN高患者的五年生存率低于VASN低患者（26.7%）。对比 83.7%）。此外，Cox分析和OS分析表明VASN是OS的独立预后因素（HR = 7.4，P值 < 0.001）和直肠癌辅助治疗效果的预测因子。我们的研究强调了VASN在降低药物敏感性中的作用激活NOTCH和MAPK通路，导致肿瘤发生和肺转移。实验和临床数据均支持活检中检测到 VASN 过度表达的直肠癌患者发生肺转移和辅助化疗耐药的风险较高。© 2024。作者。

LARC patients commonly receive adjuvant therapy, however, hidden micrometastases still limit the improvement of OS. This study aims to investigate the impact of VASN in rectal cancer with pulmonary metastasis and understand the underlying molecular mechanisms to guide adjuvant chemotherapy selection.Sequencing data from rectal cancer patients with pulmonary metastasis from Sun Yat-sen University Cancer Center (SYSUCC) and publicly available data were meticulously analyzed. The functional role of VASN in pulmonary metastasis was validated in vivo and in vitro. Coimmunoprecipitation (co-IP), immunofluorescence, and rescue experiments were conducted to unravel potential molecular mechanisms of VASN. Moreover, VASN expression levels in tumor samples were examined and analyzed for their correlations with pulmonary metastasis status, tumor stage, adjuvant chemotherapy benefit, and survival outcome.Our study revealed a significant association between high VASN expression and pulmonary metastasis in LARC patients. Experiments in vitro and in vivo demonstrated that VASN could promote the cell proliferation, metastasis, and drug resistance of colorectal cancer. Mechanistically, VASN interacts with the NOTCH1 protein, leading to concurrent activation of the NOTCH and MAPK pathways. Clinically, pulmonary metastasis and advanced tumor stage were observed in 90% of VASN-positive patients and 53.5% of VASN-high patients, respectively, and VASN-high patients had a lower five-year survival rate than VASN-low patients (26.7% vs. 83.7%). Moreover, the Cox analysis and OS analysis indicated that VASN was an independent prognostic factor for OS (HR = 7.4, P value < 0.001) and a predictor of adjuvant therapy efficacy in rectal cancer.Our study highlights the role of VASN in decreasing drug sensitivity and activating the NOTCH and MAPK pathways, which leads to tumorigenesis and pulmonary metastasis. Both experimental and clinical data support that rectal cancer patients with VASN overexpression detected in biopsies have a higher risk of pulmonary metastasis and adjuvant chemotherapy resistance.© 2024. The Author(s).