Multi-omics profiling of metastatic colorectal cancer reveals the transcriptional network of focal adhesion and immune suppression and the role of p-RPS6.
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引用次数: 0
Abstract
Background: Colorectal cancer (CRC) is one of the deadliest malignancies worldwide characterized by rapid progression, high metastasis propensity. Our study aimed to identify the driving biological factors of metastatic CRC.
Methods: We obtained frozen tumor tissues of 8 metastatic CRC (mCRC) patients and 10 non-metastatic CRC (nmCRC) patients from Ruijin Hospital for proteome analysis. FFPE tumor and adjacent normal tissues of another 8 metastatic CRC patients and 8 non-metastatic CRC patients were collected for transcriptome and whole exome sequencing. Mutational burden and signatures were revealed and differentially expressed genes and proteins were analyzed. Molecular Complex Detection was used to build the core network. KEGG and GO pathway enrichment analysis were performed. IHC staining against p-RPS6 and subsequent quantification were performed on human samples.
Results: We identified 53,917 SNPs by WES with a median of 1154 variants per sample and 23.08 mutations per megabase (Mb). We observed the mutation burdens were similar between mCRC tumor and nmCRC tumor tissues (p = 0.57), as well as the mutation frequencies of HRR and MMR related genes. All mCRC samples were affected by RTK-RAS, NOTCH and WNT pathway mutations. We constructed a 16-hub-gene network in mCRC which was characterized by dis-modulation of cell adhesion (SELE, SELL and SELP) and immune exhaustion (CXCR2, CCR7, CXCR1, CXCL13, CCL7, CCL19, CXCL11 and CD19) in mCRC tumor microenvironment. We detected 22 differentially expressed proteins, 54 phosphorylated proteins and 6 tyrosine-phosphorylated proteins between mCRC and nmCRC tumors. Phosphorylated RPS6 (p-RPS6) was the most differentially expressed protein between mCRC and nmCRC tumor tissues, which was found to be positively correlated with EMT proteins and poor prognosis in CRC. The IHC staining against p-RPS6 on human samples supported the strong expression in mCRC tumor samples.
Conclusions: We identified the key transcriptome network in mCRC and confirmed the important role for RPS6 phosphorylation in mCRC. Our study suggested that the features of mCRC tumors were not driven by gene mutations. We revealed the EMT feature and immune exhaustion of the mCRC tumor microenvironment.
期刊介绍：
Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques.
The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors.
Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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