Identification and Validation of a Malignant Cell Subset Marker-Based Polygenic Risk Score in Stomach Adenocarcinoma Through Integrated Analysis of Bulk and Single-Cell RNA Sequencing Data

Zou, Qi-Yuan; Lv, Yufeng; Gan, Zuhuan; Liao, Shulan; Zhou, Liang

doi:10.3389/fcell.2021.720649

Cited by 10 publications

(8 citation statements)

References 48 publications

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“…Zou et al . [ 55 ] also proposed complete responses to drug therapies are rare in tumours, and only some but not all subpopulations in a given tumour response to therapy. Single‐cell analysis revealed that most genes in the 28‐GPS were not only expressed in cancer cells but also in stromal cells.…”

Section: Discussionmentioning

confidence: 99%

Systematic exploration of the underlying mechanism of gemcitabine resistance in pancreatic adenocarcinoma

et al. 2022

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Resistance to gemcitabine is the main challenge of chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Hence, the development of a response signature to gemcitabine is essential for precision therapy of PDAC. However, existing quantitative signatures of gemcitabine are susceptible to batch effects and variations in sequencing platforms. Therefore, based on within‐sample relative expression ordering of pairwise genes, we developed a transcriptome‐based gemcitabine signature consisting of 28 gene pairs (28‐GPS) that could predict response to gemcitabine for PDAC at the individual level. The 28‐GPS was superior to previous quantitative signatures in terms of classification accuracy and prognostic performance. Resistant samples classified by 28‐GPS showed poorer overall survival, higher genomic instability, lower immune infiltration, higher metabolic level and higher‐fidelity DNA damage repair compared with sensitive samples. In addition, we found that gemcitabine combined with phosphoinositide 3‐kinase (PI3K) inhibitor may be an alternative treatment strategy for PDAC. Single‐cell analysis revealed that cancer cells in the same PDAC sample showed both the characteristics of sensitivity and resistance to gemcitabine, and the activation of the TGFβ signalling pathway could promote progression of PDAC. In brief, 28‐GPS could robustly determine whether PDAC is resistant or sensitive to gemcitabine, and may be an auxiliary tool for clinical treatment.

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Section: Discussionmentioning

confidence: 99%

Systematic exploration of the underlying mechanism of gemcitabine resistance in pancreatic adenocarcinoma

et al. 2022

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“…As well, the TIMER tool is a comprehensive resource designed to analyze immune cell infiltrates across diverse cancer subtypes (139). The TCGA has a publicly available human stomach adenocarcinoma (STAD) dataset containing clinical annotations along with molecular profiles that were utilized as a reference or primary dataset in several studies (25,28,36,37,41,45,133). FirebrowseR, also generated by the Broad Institute, is a database which provides access to the PanCanAtlas, containing conserved cancer gene expression data (134).…”

Section: Tools For Analyzing Gastric Cancer Scrnaseq Datamentioning

confidence: 99%

“…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). Others transcriptionally profiled "liquid biopsies" of metastatic ascites fluid taken from gastric cancer patients (44,45).…”

Section: Introductionmentioning

confidence: 99%

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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“…The advantageous difference of increased granularity is tantamount—scRNA-seq faithfully represents cellular heterogeneity by distinguishing gene expression profiles between different cell types, and even between the same cell type in different cellular states ( Lähnemann et al, 2020 ). The advances in medicine made possible by scRNA-seq are invaluable, e.g., scRNA-seq enabled Zou et al (2021) to develop a prognostic signature in gastric adenocarcinoma, Deng et al (2020) identified characteristics predicting CAR T cell therapy efficacy. Toxicology can follow suit to develop targeted therapies for the myriad of multi-cell-type health problems associated with environmental exposure to chemicals, including cancer ( Snyder, 2012 ), asthma ( Sachdeva et al, 2019 ), and infertility ( Canipari et al, 2020 ; Selvaraju et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Comparative Toxicotranscriptomics of Single Cell RNA-Seq and Conventional RNA-Seq in TCDD-Exposed Testicular Tissue

et al. 2022

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In this report, we compare the outcomes and limitations of two methods of transcriptomic inquiry on adult zebrafish testes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during sexual differentiation: conventional or bulk RNA-seq (bulk-seq) and single cell RNA sequencing (scRNA-seq) data. scRNA-seq has emerged as a valuable tool for uncovering cell type-specific transcriptome dynamics which exist in heterogeneous tissue. Our lab previously showed the toxicological value of the scRNA-seq pipeline to characterize the sequelae of TCDD exposure in testes, demonstrating that loss of spermatids and spermatozoa, but not other cell types, contributed to the pathology of infertility in adult male zebrafish exposed during sexual differentiation. To investigate the potential for technical artifacts in scRNA-seq such as cell dissociation effects and reduced transcriptome coverage, we compared bulk-sequenced and scRNA-seq-paired samples from control and TCDD-exposed samples to understand what is gained and lost in scRNA-seq vs bulk-seq, both transcriptomically and toxicologically. We hypothesized that the testes may be sensitive to tissue disruption as they contain multiple cell types under constant division and/or maturation, and that TCDD exposure may mediate the extent of sensitivity. Thus, we sought to understand the extent to which this dissociation impacts the toxicological value of data returned from scRNA-seq. We confirm that the required dissociation of individual cells from intact tissue has a significant impact on gene expression, affecting gene pathways with the potential to confound toxicogenomics studies on exposures if findings are not well-controlled and well-situated in context. Additionally, a common scRNA-seq method using cDNA amplified from the 3’ end of mRNA under-detects low-expressing transcripts including transcription factors. We confirm this, and show TCDD-related genes may be overlooked by scRNA-seq, however, this under-detection effect is not mediated by TCDD exposure. Even so, scRNA-seq generally extracted toxicologically relevant information better than the bulk-seq method in the present study. This report aims to inform future experimental design for transcriptomic investigation in the growing field of toxicogenomics by demonstrating the differential information extracted from sequencing cells—despite being from the same tissue and exposure scheme—is influenced by the specific protocol used, with implications for the interpretation of exposure-induced risk.

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Identification and Validation of a Malignant Cell Subset Marker-Based Polygenic Risk Score in Stomach Adenocarcinoma Through Integrated Analysis of Bulk and Single-Cell RNA Sequencing Data

Cited by 10 publications

References 48 publications

Systematic exploration of the underlying mechanism of gemcitabine resistance in pancreatic adenocarcinoma

Systematic exploration of the underlying mechanism of gemcitabine resistance in pancreatic adenocarcinoma

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

Comparative Toxicotranscriptomics of Single Cell RNA-Seq and Conventional RNA-Seq in TCDD-Exposed Testicular Tissue

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