Vasorin (VASN) overexpression promotes pulmonary metastasis and resistance to adjuvant chemotherapy in patients with locally advanced rectal cancer

• Published in: Journal of translational medicine Vol. 22; no. 1; pp. 742 - 19
• Main Authors: Kang, Da, Huang, Shanshan, Liao, Yijun, Mi, Siyuan, Zhou, Jingying, Feng, Yu, Huang, Riming, Lu, Zhen-Hai, Pan, Z Z, Ma, Wenjuan, Chen, Gong, Yue, Jia-Xing, Huang, Jingxiu, Zhang, R X
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.08.2024; BioMed Central; BMC
• Subjects: Adjuvant therapy; Adjuvant treatment; Analysis; Animals; Cancer; Cancer patients; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy, Adjuvant; Colorectal cancer; Drug resistance; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Neoplastic; Health aspects; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Male; MAP Kinase Signaling System - drug effects; MAPK pathway; Metastasis; Mice, Nude; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Middle Aged; NOTCH pathway; Oncology, Experimental; Pulmonary metastasis; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Rectal cancer; Rectal Neoplasms - drug therapy; Rectal Neoplasms - genetics; Rectal Neoplasms - metabolism; Rectal Neoplasms - pathology; MAPK pathway; Pulmonary metastasis; NOTCH pathway; Rectal cancer; Adjuvant therapy
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-024-05473-4

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.