Single-cell transcriptomic profiling unravels the adenoma-initiation role of protein tyrosine kinases during colorectal tumorigenesis

Abstract

The adenoma-carcinoma sequence is a well-accepted roadmap for the development of sporadic colorectal cancer. However, cellular heterogeneity in aberrant epithelial cells limits our understanding of carcinogenesis in colorectal tissues. Here, we performed a single-cell RNA sequencing survey of 54,788 cells from patient-matched tissue samples, including blood, normal tissue, para-cancer, polyp, and colorectal cancer. At each stage of carcinogenesis, we characterized cell types, transcriptional signatures, and differentially expressed genes of distinct cell populations. The molecular signatures of epithelial cells at normal, benign, and malignant stages were defined at the single-cell scale. Adenoma and carcinoma precursor cell populations were identified and characterized followed by validation with large cohort biopsies. Protein tyrosine kinases (PTKs) BMX and HCK were identified as potential drivers of adenoma initiation. Specific BMX and HCK upregulations were observed in adenoma precursor cell populations from normal and adenoma biopsies. Overexpression of BMX and HCK significantly promoted colorectal epithelial cell proliferation. Importantly, in the organoid culture system, BMX and HCK upregulations resulted in the formation of multilayered polyp-like buds protruding towards the organoid lumen, mimicking the pathological polyp morphology often observed in colorectal cancer. Molecular mechanism analysis revealed that upregulation of BMX or HCK activated the JAK-STAT pathway. In conclusion, our work improved the current knowledge regarding colorectal epithelial evolution during carcinogenesis at the single-cell resolution. These findings may lead to improvements in colorectal cancer diagnosis and treatment.

Loss of MHC-I antigen presentation correlated with immune checkpoint blockade tolerance in MAPK inhibitor-resistant melanoma

“…Mouse melanoma single-cell transcriptomic gene expression data were obtained through the GEO database (GSE126714), which contains single-cell transcriptomic data from 618 tumor cells, 222 T/NK cells, 794 macrophages, and 762 monocytes in the BRAF-targeted therapy before treatment, during the response, and the drug resistance (Long et al, 2019). Singlecell data were analyzed and visualized using Seurat (v3.1.2) as described in our previously published article (Stuart et al, 2019;Zheng et al, 2022).…”

Single-Cell RNA Sequencing Reveals the Role of Epithelial Cell Marker Genes in Predicting the Prognosis of Colorectal Cancer Patients

“…Relevant clinical information related to the CRC samples is provided in Supplementary Table S1. The dataset comprises four CRC samples, four adenoma samples, three normal tissue samples, one paracancer sample, and one blood sample [21]. Tissue samples other than the CRC samples were not considered in this study.…”

Exploring the Interplay between Metabolism and Tumor Microenvironment Based on Four Major Metabolism Pathways in Colon Adenocarcinoma

“…Expression profiles with fragments per kilobase million (FPKM) format were transformed into transcript per million (TPM) format. GSE17536 [ 18 ] and GSE161277 [ 19 ] datasets were downloaded from Gene Expression Omnibus (GEO) database ( https://www.ncbi.nlm.nih.gov/geo/ ). Four metabolism pathways (glycolysis, PPP, FAO, and glutaminolysis) were obtained from Molecular Signatures Database [ 20 ] (MSigDB, https://www.gsea-msigdb.org/gsea/msigdb/ ).…”