Dataset Information

Single-cell RNA-seq reveals transcriptional landscape and intratumor heterogenicity in gallbladder cancer liver metastasis microenvironment.

ABSTRACT:

Background

Gallbladder cancer (GBC) is a highly aggressive biliary epithelial malignancy. The median survival time of GBC patients was less than 1 year. Tumor invasion and metastasis are the major cause of high mortality of GBC patients. However, the molecular mechanisms involved in GBC metastases are still unclear.

Methods

We performed 10X genomics single-cell RNA sequencing (scRNA-seq) on GBC liver metastasis tissue to evaluate the characteristics of the GBC liver metastasis microenvironment.

Results

In this study, 8 cell types, a total of 7,788 cells, including T cells, B cells, malignant cells, fibroblasts, endothelial cells, macrophages, dendritic cells (DCs), and mast cells were identified. Malignant cells displayed a high degree of intratumor heterogenicity, while neutrophils were found to promote GBC cell proliferation, migration, and invasion. Furthermore, cytotoxic cluster of differentiation (CD8⁺) T cells became exhausted and CD4⁺ regulatory T cells (Tregs) exhibited immunosuppressive characteristics. Macrophages played an important role in the tumor microenvironment (TME). We identified three distinct macrophage subsets and emergent M2 polarization. We also found that cancer-associated fibroblasts exhibited heterogeneity and may be associated with GBC metastasis.

Conclusions

Although preliminary in nature, our study provides a landscape view at the single-cell level. These results offer a unique perspective into understanding the liver metastasis of GBC.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8184464 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Publications

Single-cell RNA-seq reveals transcriptional landscape and intratumor heterogenicity in gallbladder cancer liver metastasis microenvironment.

Zhang Yigang Y You Wen-Hua WH Li Xiangyu X Wang Peng P Sha Bowen B Liang Yuan Y Qiu Jiannan J Zhou Jinren J Hu Haoran H Lu Ling L

Annals of translational medicine 20210501 10

<h4>Background</h4>Gallbladder cancer (GBC) is a highly aggressive biliary epithelial malignancy. The median survival time of GBC patients was less than 1 year. Tumor invasion and metastasis are the major cause of high mortality of GBC patients. However, the molecular mechanisms involved in GBC metastases are still unclear.<h4>Methods</h4>We performed 10X genomics single-cell RNA sequencing (scRNA-seq) on GBC liver metastasis tissue to evaluate the characteristics of the GBC liver metastasis mic ...[more]

PMID: 34164523

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Project description:Triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy (NAC) represents a major clinical challenge; therefore, delineating tumor heterogeneity can provide novel insight into resistance mechanisms and potential therapeutic targets. Herein, we identified the transcriptional landscape associated with TNBC resistance to NAC at the single-cell level by analyzing publicly available transcriptome data from more than 5,000 single cells derived from four extinction (responders) and four persistence (non-responders) patients, revealing remarkable tumor heterogeneity. Employing iterative clustering and guide-gene selection (ICGS) and uniform manifold approximation and projection (UMAP), we classified TNBC single cells into several clusters based on their distinct gene signatures. The presence of clusters indicative of immune cell activation was a hallmark of the extinction group pre-NAC, while post NAC, the extinction tissue consisted mostly of breast, omental fat, and fibroblasts. The persistent gene signatures of pre-NAC resembled the gene signature of lung epithelial, mammary, and salivary glands and acute myeloid leukemia blast cells, which were associated with enhanced cellular movement and activation of FOXM1, NOTCH1, and MYC and suppression of tumor necrosis factor (TNF) and IFNG mechanistic networks. Multivariate survival analysis identified persistence-derived three-gene signature (KIF5BhighHLA-ClowIGHG2low) predictive of relapse-free survival (hazard ratio [HR]: 2.2 [1.6-3.2, p < 0.0001]) in a second cohort of 360 TNBC patients. Mechanistically, loss of function of several upregulated genes in the persistent group (BYSL, FDPS, ENO1, MED20, MRPL9, MRPL37, NDUFB11, PMVK, MYC, and GSTP1) inhibited MDA-MB-231 and BT-549 TNBC models' colony-forming unit (CFU) potential and enhanced their sensitivity to paclitaxel. Our data unraveled the transcriptional portrait associated with NAC resistance, identified several key genes, and suggested their potential utilization as prognostic markers and therapeutic targets in TNBC.

Dataset Information

Single-cell RNA-seq reveals transcriptional landscape and intratumor heterogenicity in gallbladder cancer liver metastasis microenvironment.

Background

Methods

Results

Conclusions

Publications

Single-cell RNA-seq reveals transcriptional landscape and intratumor heterogenicity in gallbladder cancer liver metastasis microenvironment.

Similar Datasets

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