Investigating the Cell Origin and Liver Metastasis Factors of Colorectal Cancer by Single-Cell Transcriptome Analysis

被引：0

作者：

Sha, Zhilin ^{[1
]}

Gao, Qingxiang ^{[1
]}

Wang, Lei ^{[2
]}

An, Ni ^{[3
]}

Wu, Yingjun ^{[1
]}

Wei, Dong ^{[4
]}

Wang, Tong ^{[5
]}

Liu, Chen ^{[1
,6
]}

Shen, Yang ^{[1
,6
]}

机构：

[1] Naval Med Univ, Eastern Hepatobiliary Surg Hosp, Dept Biliary Tract Surg 1, Shanghai, Peoples R China

[2] Yancheng Hosp Tradit Chinese Med, Dept Gen Surg, Yancheng, Jiangsu, Peoples R China

[3] Chinese Peoples Liberat Army Gen Hosp, Med Ctr 8, Dept Anesthesiol, Beijing, Peoples R China

[4] 1 Peoples Hosp Pinghu, Dept Gen Surg, Ward 2, Pinghu, Zhejiang, Peoples R China

[5] 32295 Troop Chinese PLA, Dept Anesthesiol, Liaoyang, Peoples R China

[6] Naval Med Univ, Eastern Hepatobiliary Surg Hosp, 700 North Moyu Rd, Shanghai 201823, Peoples R China

来源：

ONCOTARGETS AND THERAPY | 2024年 / 17卷

关键词：

colorectal cancer; liver metastasis; single-cell sequencing; SOX4; prognostic; PROGRESSION; FEATURES;

D O I：

10.2147/OTT.S454295

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Background: Colorectal cancer (CRC) is one of the deadliest causes of death by cancer worldwide. Liver metastasis (LM) is the main cause of death in patients with CRC. Therefore, identification of patients with the greatest risk of liver metastasis is critical for early treatment and reduces the mortality of patients with colorectal cancer liver metastases. Methods: Initially, we characterized cell composition through single-cell transcriptome analysis. Subsequently, we employed copy number variation (CNV) and pseudotime analysis to delineate the cellular origins of LM and identify LM-related epithelial cells (LMECs). The LM-index was constructed using machine learning algorithms to forecast the relative abundance of LMECs, reflecting the risk of LM. Furthermore, we analyzed drug sensitivity and drug targeted gene expression in LMECs and patients with a high risk of LM. Finally, functional experiments were conducted to determine the biological roles of metastasis-related gene in vitro. Results: Single-cell RNA sequencing analysis revealed different immune landscapes between primary CRC and LM tumor. LM originated from chromosomal variants with copy number loss of chr1 and chr6p and copy number gain of chr7 and chr20q. We identified the LMECs cluster and found LM-associated pathways such as Wnt/beta-catenin signaling and KRAS signaling. Subsequently, we identified ten metastasis-associated genes, including SOX4, and established the LM-index, which correlates with poorer prognosis, higher stage, and advanced age. Furthermore, we screened two drugs as potential candidates for treating LM, including Linsitinib_1510, Lapatinib_1558. Immunohistochemistry results demonstrated significantly elevated SOX4 expression in tumor samples compared to normal samples. Finally, in vitro experiments verified that silencing SOX4 significantly inhibited tumor cell migration and invasion. Conclusion: This study reveals the possible cellular origin and driving factors of LM in CRC at the single cell level, and provides a reference for early detection of CRC patients with a high risk of LM.

引用

页码：345 / 358

页数：14