Single-cell analysis of gastric pre-cancerous and cancer lesions reveals cell lineage diversity and intratumoral heterogeneity

Kim, Jihyun; Park, Charny; Kim, Kwang H.; Kim, Eun Hye; Kim, Hyunki; Woo, Jong Kyu; Seong, Je Kyung; Nam, Ki Taek; Lee, Yong Chan; Cho, Soo Young

doi:10.1038/s41698-022-00251-1

Cited by 71 publications

(72 citation statements)

References 45 publications

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“…Enrichment of these genes and an identified proximity to exhausted CTLs in lymphoid structures suggest that iCAFs can regulate lymphocyte function (24). found that diffuse gastric cancer tissues showed a high prevalence of iCAFs compared to intestinal gastric cancer tissues, and overall iCAF number increased in gastric cancer compared to normal tissue (23). The same study also found a correlation between iCAFs and pro-stemness of tumors, suggesting that these cells promote cancer stem cell formation.…”

Section: Fibroblasts and Endothelial Cellsmentioning

confidence: 84%

“…Other stromal cells within the TME, like fibroblasts and endothelial cells, also likely play immunological roles in tumor progression. CAFs and endothelial cells have been found to play distinct roles in regulating the antitumor immune response and promoting cancer growth and metastasis (23,24,26,39). Epithelial cell responses to these various inflammatory signals have displayed mixed findings with regards to promotion and inhibition of tumor progression, especially when focusing on different time points of disease and distinct gastric cancer types.…”

Section: Discussionmentioning

confidence: 99%

“…Two distinct fibroblast phenotypes were identified in scRNAseq gastric cancer datasets (23,24,34). One is an extracellular matrix cancer-associated fibroblast (eCAF), and another is an inflammatory cancer-associated fibroblast (iCAF).…”

Section: Fibroblasts and Endothelial Cellsmentioning

confidence: 99%

“…The program inferCNV, available through the Broad Institute, has been used by several groups to identify copy number alterations of malignant cells within scRNAseq data (18,21,22,44,45,124,137). Many other programs are also useful to estimate chromosomal alterations within cancer scRNAseq datasets, viz., LIAYSON, 10X supported VarTrix, GISTIC2, CopyKAT, and Mutect2 (23,25,44,55,(125)(126)(127). ABSOLUTE can be used to infer intratumoral heterogeneity (28,128,138).…”

Section: Tools For Analyzing Gastric Cancer Scrnaseq Datamentioning

confidence: 99%

“…Among the published scRNAseq gastric cancer works, it is apparent that they have undertaken various approaches to their studies. Most groups obtained primary gastric cancer tissues from patients to generate scRNAseq data (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Some utilized previously published primary tumor datasets for further analysis (36)(37)(38)(39)(40)(41)(42)(43).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

Hoft

Pherson²,

DiPaolo³

2022

Front. Immunol.

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Single-cell RNA sequencing (scRNAseq) technology is still relatively new in the field of gastric cancer immunology but gaining significant traction. This technology now provides unprecedented insights into the intratumoral and intertumoral heterogeneities at the immunological, cellular, and molecular levels. Within the last few years, a volume of publications reported the usefulness of scRNAseq technology in identifying thus far elusive immunological mechanisms that may promote and impede gastric cancer development. These studies analyzed datasets generated from primary human gastric cancer tissues, metastatic ascites fluid from gastric cancer patients, and laboratory-generated data from in vitro and in vivo models of gastric diseases. In this review, we overview the exciting findings from scRNAseq datasets that uncovered the role of critical immune cells, including T cells, B cells, myeloid cells, mast cells, ILC2s, and other inflammatory stromal cells, like fibroblasts and endothelial cells. In addition, we also provide a synopsis of the initial scRNAseq findings on the interesting epithelial cell responses to inflammation. In summary, these new studies have implicated roles for T and B cells and subsets like NKT cells in tumor development and progression. The current studies identified diverse subsets of macrophages and mast cells in the tumor microenvironment, however, additional studies to determine their roles in promoting cancer growth are needed. Some groups specifically focus on the less prevalent ILC2 cell type that may contribute to early cancer development. ScRNAseq analysis also reveals that stromal cells, e.g., fibroblasts and endothelial cells, regulate inflammation and promote metastasis, making them key targets for future investigations. While evaluating the outcomes, we also highlight the gaps in the current findings and provide an assessment of what this technology holds for gastric cancer research in the coming years. With scRNAseq technology expanding rapidly, we stress the need for periodic review of the findings and assess the available scRNAseq analytical tools to guide future work on immunological mechanisms of gastric carcinogenesis.

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Section: Fibroblasts and Endothelial Cellsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Fibroblasts and Endothelial Cellsmentioning

confidence: 99%

Section: Tools For Analyzing Gastric Cancer Scrnaseq Datamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

Hoft

Pherson²,

DiPaolo³

2022

Front. Immunol.

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Single cell RNA‐sequencing: A powerful yet still challenging technology to study cellular heterogeneity

Elshenawy

Sheldon

et al. 2022

BioEssays

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Almost all biomedical research to date has relied upon mean measurements from cell populations, however it is well established that what it is observed at this macroscopic level can be the result of many interactions of several different single cells. Thus, the observable macroscopic ‘average’ cannot outright be used as representative of the ‘average cell’. Rather, it is the resulting emerging behaviour of the actions and interactions of many different cells. Single‐cell RNA sequencing (scRNA‐Seq) enables the comparison of the transcriptomes of individual cells. This provides high‐resolution maps of the dynamic cellular programmes allowing us to answer fundamental biological questions on their function and evolution. It also allows to address medical questions such as the role of rare cell populations contributing to disease progression and therapeutic resistance. Furthermore, it provides an understanding of context‐specific dependencies, namely the behaviour and function that a cell has in a specific context, which can be crucial to understand some complex diseases, such as diabetes, cardiovascular disease and cancer. Here, we provide an overview of scRNA‐Seq, including a comparative review of emerging technologies and computational pipelines. We discuss the current and emerging applications and focus on tumour heterogeneity a clear example of how scRNA‐Seq can provide new understanding of a complex disease. Additionally, we review the limitations and highlight the need of powerful computational pipelines and reproducible protocols for the broader acceptance of this technique in basic and clinical research.

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The role of long non‐coding RNA Maternally Expressed Gene 3 in cancer‐associated fibroblasts at single cell pan‐cancer level

Zhou,

Yan,

Deng

et al. 2024

Interdisciplinary Medicine

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Long non‐coding RNAs (lncRNAs) can crucially regulate activation and transformation of cancer‐associated fibroblasts (CAFs) but have not been systematically investigated at single cell resolution. Here, by utilizing integrated single‐cell sequencing datasets, we screened the aberrantly expressed lncRNAs in CAFs, which are the major component of tumor microenvironment. Our findings revealed a consistent CAF‐specific downregulation of Maternally Expressed Gene 3 (MEG3) expression and increased MEG3+ proportion at the pan‐cancer level, which may be attributed to m6A‐related post‐transcriptional modifications. Through activation trajectory analysis of the major CAF subtypes, it was determined that elevated MEG3 expression in CAFs leads to an increase in PDGFRA expression. This, in turn, promotes CAF activation and transformation into an MEG3+ adipogenic CAF (MACAF) subtype, which is more sensitive to Dasatinib. MACAF‐related cell–cell interactions highlighted that MACAF could enhance the epithelial‐mesenchymal transition process in tumor cells via the TGF‐β pathway, promoting tumor cell migration and possibly contributing to tumor progression and invasiveness. Notably, patients with higher MACAF scores experience unfavorable prognoses and poor response rates to checkpoint inhibitor‐based immunotherapy, suggesting a correlation between MACAF and immunosuppressive microenvironment shaping. Our findings provide novel insights of the MEG3 in CAF activation and highlight the potential value of the MACAF score for therapeutic strategies design involving Dasatinib and immunotherapy.

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Single-cell analysis of gastric pre-cancerous and cancer lesions reveals cell lineage diversity and intratumoral heterogeneity

Cited by 71 publications

References 45 publications

Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

Single cell RNA‐sequencing: A powerful yet still challenging technology to study cellular heterogeneity

The role of long non‐coding RNA Maternally Expressed Gene 3 in cancer‐associated fibroblasts at single cell pan‐cancer level

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