Dataset Information

Single-cell Transcriptomics Reveals Early Molecular and Immune Alterations Underlying the Serrated Neoplasia Pathway Toward Colorectal Cancer.

ABSTRACT:

Background & aims

Approximately one-third of colorectal cancers develop from serrated lesions (SLs), including hyperplastic polyp (HP), sessile serrated lesion (SSL), traditional serrated adenoma (TSA), and SSL with dysplasia (SSLD) through the serrated neoplasia pathway, which progresses faster than the conventional adenoma-carcinoma pathway. We sought to depict the currently unclarified molecular and immune alterations by the single-cell landscape in SLs.

Methods

We performed single-cell RNA sequencing of 16 SLs (including 4 proximal HPs, 5 SSLs, 2 SSLDs, and 5 TSAs) vs 3 normal colonic tissues.

Results

A total of 60,568 high-quality cells were obtained. Two distinct epithelial clusters with redox imbalance in SLs were observed, along with upregulation of tumor-promoting SerpinB6 that regulated ROS level. Epithelial clusters of SSL and TSA showed distinct molecular features: SSL-specific epithelium manifested overexpressed proliferative markers with Notch pathway activation, whereas TSA-specific epithelium showed Paneth cell metaplasia with aberrant lysozyme expression. As for immune contexture, enhanced cytotoxic activity of CD8⁺ T cells was observed in SLs; it was mainly attributable to increased proportion of CD103⁺CD8⁺ tissue-resident memory T cells, which might be regulated by retinoic acid metabolism. Microenvironment of SLs was generally immune-activated, whereas some immunosuppressive cells (regulatory T cells, anti-inflammatory macrophages, MDK⁺IgA⁺ plasma cells, MMP11-secreting PDGFRA⁺ fibroblasts) also emerged at early stage and further accumulated in SSLD.

Conclusion

Epithelial, immune, and stromal components in the serrated pathway undergo fundamental alterations. Future molecular subtypes of SLs and potential immune therapy might be developed.

SUBMITTER: Zhou YJ

PROVIDER: S-EPMC9791140 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Single-cell Transcriptomics Reveals Early Molecular and Immune Alterations Underlying the Serrated Neoplasia Pathway Toward Colorectal Cancer.

Zhou Yu-Jie YJ Lu Xiao-Fan XF Chen Huimin H Wang Xin-Yuan XY Cheng Wenxuan W Zhang Qing-Wei QW Chen Jin-Nan JN Wang Xiao-Yi XY Jin Jing-Zheng JZ Yan Fang-Rong FR Chen Haoyan H Li Xiao-Bo XB

Cellular and molecular gastroenterology and hepatology 20221008 2

<h4>Background & aims</h4>Approximately one-third of colorectal cancers develop from serrated lesions (SLs), including hyperplastic polyp (HP), sessile serrated lesion (SSL), traditional serrated adenoma (TSA), and SSL with dysplasia (SSLD) through the serrated neoplasia pathway, which progresses faster than the conventional adenoma-carcinoma pathway. We sought to depict the currently unclarified molecular and immune alterations by the single-cell landscape in SLs.<h4>Methods</h4>We performed si ...[more]

PMID: 36216310

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Project description:BackgroundDysregulation of erythropoietin-producing hepatoma (Eph) proteins in human cancers is extensively documented but not clear in colorectal cancer (CRC). In this study, we aimed to investigate the role of Notch signaling pathway and epigenetic modification of EPHB2 and EPHB4 expression in serrated neoplasia development.MethodsThe expression of EPHB2 and EPHB4 in CRC clinical specimens and cell lines were determined by immunohistochemistry, Western blot, and real-time PCR. Cell proliferation and invasion were evaluated by MTT and chamber kits, luciferase assay and co-immunoprecipitation were used to detect the transcriptional regulation and protein-protein interactions, respectively. The immunofluorescence assay was employed to confirm the subcellular location of Notch intracellular domain (NICD), and chromatin immunoprecipitation assay was implied to detect the modification types of H3K4me3 and H3K27me3. Mice xenograft model was used to detect the in vivo effects of EPHB2 and EPHB4 genes on cell growth.ResultsIn CRC clinical specimens and cell lines, we found that EPHB2 was significantly decreased, while EPHB4 was elevated in the CRC tissues, and these aberrant expression manners correlated with worse overall survival rates in the clinic. When the EPHB2 and EPHB4 expressions were manipulated by overexpression or knockdown in the SW620 cells, the cell proliferation and invasion were obviously suppressed, whereas EPHB2 knockdown or EPHB4 overexpression showed the opposite phenotypes. We also found that Notch signaling pathway was abnormally activated and treatment of Notch signaling ligand human Jagged1 peptide downregulated EPHB2 and upregulated EPHB4 in the SW620 cells, as well as promoted the chromatin modification protein Jumonji domain-containing protein-3 (JMJD3) cytonuclear trans-localization with the NICD, which indicated that NICD brought JMJD3 to the EPHB4 enhancer region to decrease the H3K27me3 level.ConclusionTaken together, we provide a new mechanistic option in understanding the role of Notch signaling and the roles of EPHB2 and EPHB4 in CRC.

Dataset Information

Single-cell Transcriptomics Reveals Early Molecular and Immune Alterations Underlying the Serrated Neoplasia Pathway Toward Colorectal Cancer.

Background & aims

Methods

Results

Conclusion

Publications

Single-cell Transcriptomics Reveals Early Molecular and Immune Alterations Underlying the Serrated Neoplasia Pathway Toward Colorectal Cancer.

Similar Datasets

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