Genome-wide CRISPR screens define determinants of epithelial-mesenchymal transition mediated immune evasion by pancreatic cancer cells

Science Advances, Journal Year: 2023, Volume and Issue: 9(28)

Published: July 14, 2023

The genetic circuits that allow cancer cells to evade immune killing via epithelial mesenchymal plasticity remain poorly understood. Here, we showed mesenchymal-like (Mes) KPC3 pancreatic were more resistant cytotoxic T lymphocyte (CTL)-mediated than the parental epithelial-like (Epi) and used parallel genome-wide CRISPR screens assess molecular underpinnings of this difference. Core CTL-evasion genes (such as IFN-γ pathway components) clearly evident in both types. Moreover, identified validated multiple Mes-specific regulators cytotoxicity, such Egfr Mfge8. Both significantly higher expressed Mes cells, their depletion sensitized CTL-mediated killing. Notably, secreted Mfge8 inhibit proliferation CD8+ production TNFα. Clinically, increased expression was correlated with a worse prognosis. Thus, use Egfr-mediated intrinsic Mfge8-mediated extrinsic mechanisms facilitate escape from cells.

Language: Английский

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Uncovering immune cell heterogeneity in hepatocellular carcinoma by combining single-cell RNA sequencing with T-cell receptor sequencing

World Journal of Hepatology, Journal Year: 2025, Volume and Issue: 17(2)

Published: Feb. 20, 2025

BACKGROUND Understanding the status and function of tumor-infiltrating immune cells is essential for improving immunotherapeutic effects predicting clinical response in human patients with carcinoma. However, little known about cells, corresponding research results hepatocellular carcinoma (HCC) are limited. AIM To investigate potential biomarker genes that important development HCC to understand how cell subsets react throughout this process. METHODS Using single-cell RNA sequencing T-cell receptor sequencing, heterogeneity functions subpopulations from tissue normal adjacent carcinoma, as well their possible interactions, were analyzed. RESULTS Eight clusters analyzed identified using bioinformatics, including six typical major two newly clusters, among which Fc epsilon 1G+ T characterized by upregulation 1G, tyrosine kinase binding protein, delta constant, whereas metallothionein 1E+ proliferated significantly tumors. Differentially expressed genes, such regulator cycle, cysteine serine rich nuclear protein 1, SMAD7 1E, upregulated tumors have biomarkers. In association analysis, we inferred clonal expansion characteristics each cluster patients. CONCLUSION We lymphocyte critical revealed amplification infiltrating cells. These data provide valuable resources understanding HCC.

Language: Английский

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“In medio stat virtus”: Insights into hybrid E/M phenotype attitudes

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: Nov. 18, 2022

Epithelial-mesenchymal plasticity (EMP) refers to the ability of cells dynamically interconvert between epithelial (E) and mesenchymal (M) phenotypes, thus generating an array hybrid E/M intermediates with mixed E M features. Recent findings have demonstrated how these rather than fully play key roles in most physiological pathological processes involving EMT. To this regard, onset state coincides highest stemness gene expression is involved differentiation either normal cancer stem cells. Moreover, are responsible for wound healing create a favorable immunosuppressive environment tissue regeneration. Nevertheless, metastatic process increasing survival, apoptosis therapy resistance The present review aims describe main features emerging concepts regulating EMP formation by describing differences similarities In particular, comprehension biology will surely advance our understanding their they could be exploited improve regeneration repair.

Language: Английский

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Identification and Characterization of Metastasis‐Initiating Cells in ESCC in a Multi‐Timepoint Pulmonary Metastasis Mouse Model

Advanced Science, Journal Year: 2024, Volume and Issue: 11(30)

Published: June 12, 2024

Metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. Single-cell RNA sequencing analyses are applied investigate lung metastatic ESCC cells isolated from pulmonary metastasis mouse model at multiple timepoints characterize early microenvironment. A small population of parental KYSE30 line (Cluster S) resembling metastasis-initiating (MICs) identified because they survive and colonize sites. Differential expression profile comparisons between Cluster S other subpopulations a panel 7 signature genes (MIS), including CD44 TACSTD2, represent MICs in ESCC. Functional studies demonstrated (CD44

Language: Английский

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Cancer cell plasticity defines response to immunotherapy in cutaneous squamous cell carcinoma

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 24, 2024

Abstract Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune (IC) ligand profile according to features, dictating IC pathways involved evasion. Epithelial cells, through PD-1/PD-L1 pathway, mesenchymal CTLA-4/CD80 TIGIT/CD155 pathways, differentially block antitumor responses determine response ICB therapies. Accordingly, anti-PD-L1/TIGIT combination is most effective strategy blocking growth cSCCs that contain both epithelial cells. The expression E-cadherin/Vimentin/CD80/CD155 proteins cSCC, HNSCC melanoma patient samples predicts anti-PD-1/PD-L1 therapy. Collectively, our findings indicate selection therapies should take into account features

Language: Английский

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