Single-Cell RNA Sequencing Reveals Multiple Pathways and the Tumor Microenvironment Could Lead to Chemotherapy Resistance in Cervical Cancer

Gu, Meijia; He, Tao; Yuan, Yuncong; Duan, Suling; Li, Xin; Shen, Chao

doi:10.3389/fonc.2021.753386

Cited by 9 publications

(13 citation statements)

References 75 publications

(76 reference statements)

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“…Unlike the high infiltration of tissue-resident CD8+ T cell, tumors exhibited the most high infiltration of exhausted CD8+ T cells, which represented a dysfunction. Similar to our results, recent studies by Gu et al reported that tumor tissue exhibited high enrichment of CD8 T cells with high expression level of immune checkpoint genes such as LAG3, PDCD1 and HAVCR2/TIM3 in CC tissue (43). In this study, we found that these cells also exerted indirect cytotoxicity by secreting chemotaxis, such as CCL1, CCL5, CLL11 and CX3CR1, which can attract NK cells, T cells and immature DCs to TME lesion.…”

Section: Discussionsupporting

confidence: 91%

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Dissecting the Single-Cell Transcriptome Network of Immune Environment Underlying Cervical Premalignant Lesion, Cervical Cancer and Metastatic Lymph Nodes

Hua

2022

Front. Immunol.

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Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

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Section: Discussionsupporting

confidence: 91%

“…Therefor, the results should be interpreted with caution. Nevertheless, unlike published studies (43,55), to the best of our knowledge, this study first provided an important understanding of TME at different stages of CC progression.…”

Section: Discussionmentioning

confidence: 83%

Dissecting the Single-Cell Transcriptome Network of Immune Environment Underlying Cervical Premalignant Lesion, Cervical Cancer and Metastatic Lymph Nodes

Hua

2022

Front. Immunol.

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“…Overall, single-cell sequencing is currently being used to build global cellular landscapes and identify disease identity markers. Many applications of single-cell sequencing in the tumor microenvironment as well as the immune microenvironment have been documented in recent studies (Gu et al, 2021;Wang et al, 2021b). Because tumors are extremely diverse, this diversity has a significant impact on disease development and therapeutic efficacy (Vasudev and Reynolds, 2014).…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Sequencing Yields Insights in the Evolution of Foot-and-Mouth Disease Virus Persistent Infection

Yuan

Wang

et al. 2022

Front. Cell. Infect. Microbiol.

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Foot-and-mouth disease virus (FMDV) could cause acute infection in host cells, or they could coexist with host cells to generate persistent infection. In persistent infection, the virus could survive for a long time in the host and could be transmitted between different host cells. In the case of FMDV-persistent infection cell line, there is a remarkable significant cellular heterogeneity in the FMDV-persistent infection cell line due to differences of viral load in the individual cells within the cell line. However, the mechanisms of FMDV-persistent infection are not well understood. It is now generally accepted that multiple factors contribute to the coevolution of viruses and cells during the course of persistent infection. The outcome would influence the development of persistent FMDV infection conjointly, reaching a state of equilibrium ultimately. Therefore, in order to elucidate the mechanism of cellular heterogeneity in FMDV-persistent infection cell line, single-cell sequencing was performed on BHK-Op, and pseudotime trajectory plot was draw through cell cluster. Based on the cell clusters, we predicted the development and progression of the FMDV-persistent infection. It could be well explained by the fact that, in BHK-Op cells, there are a fraction of infected cells and a fraction of virus-exposed but uninfected bystander cells. By further comparing the transcripts in cell clusters, we found that these genes were involved in changes in ribosome biogenesis, cell cycle, and intracellular signaling including the interferon signaling pathway and mitogen-activated protein kinase (MAPK) signaling pathway. Through comprehensive cross-tabulation analysis of differential expressed genes in various cluster of cells, we identified a high association of Fos, a downstream transcription factor of the MAPK/extracellular signal–regulated kinase (ERK) signaling pathway, with viral replication during the formation of FMDV-persistent infection. Through the further study of Fos, we found that downregulation of Fos facilitates viral clearance during FMDV-persistent infection. Upregulation of c-Raf, which is the upstream of the MAPK/ERK signaling pathway, could promote FMDV replication through downregulation of Fos. Our research is the first to provide insight into the mechanism of the formation FMDV-persistent infection through single-cell sequencing using persistent infection cell line. Pseudotime trajectory analysis was the first time to apply for FMDV-persistent infection cell line. Our work highlights the detailed overview of the evolution of FMDV-persistent infection. We also analyzed the differential expressed genes in the replication or elimination of FMDV within the host. We found that the MAPK/ERK signaling pathway and its downstream transcription factor Fos play an important role in FMDV-persistent infection.

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“…A recent scRNA-seq analysis found the enrichment of PI3K/AKT pathway supported by differentially expressed genes between chemoresistant and chemosensitive CC patients [15]. The mutation in NFKB1 (G430E) was shown to signi cantly increase mutant allele frequency after radiotherapy, indicating its role as a potential molecular target in CC radiation therapy [21].…”

Section: Introductionmentioning

confidence: 99%

“…The TME establishment is a slow process, and recent studies showed that earlyand late-stages of multiple cancer TME are heterogenetic and functionally different [9][10][11], though the TME of both early-and late-stage colorectal cancer has been shown to be equally immunosuppressive [12]. Many cells show heterogeneity in both phenotypes and functions during early versus late stage of cancer development, especially when multi-omics and single-cell RNA sequencing (scRNA-seq) techniques were used to analyse the landscape of the TME [13][14][15][16]. For example, neutrophils show heterogeneity in both phenotypes and functions during early versus late stage of cancer development [17,18].…”

Section: Introductionmentioning

confidence: 99%

Single-cell transcriptomics and deep tissue proteomics reveal distinct tumour microenvironment present in stage-I and II cervical cancer

Liu

Zhang

et al. 2022

Preprint

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Background Cervical cancer (CC) is the 3rd most common cancer in women and the 4th leading cause of deaths in gynaecological malignancies, yet the exact progression of CC is inconclusive, mainly due to the high complexity the changing tumour microenvironment (TME) at different stages of tumorigenesis. Importantly, a detailed comparative single-cell transcriptomic analysis of tumour microenvironment (TME) of CC patients at different stages is lacking. Methods In this study, a total of 42,928 and 29,200 cells isolated from the tumour tissues of stage-I and II CC patients and subjected to single-cell RNA sequencing (scRNA-seq) analysis. The cell heterogeneity and functions were comparatively investigated using bioinformatic tools. In addition, label-free quantitative mass spectrometry based proteomic analysis was carried out. The proteome profiles of stage-I and II CC patients were compared, and an integrative analysis with the scRNA-seq was performed. Results Compared with the stage-I CC (CCI) patients, the immune response relevant signalling pathways were largely suppressed in various immune cells of the stage-II CC (CCII) patients, yet the signalling associated with cell and tissue development was enriched, as well as metabolism for energy production suggested by the upregulation of genes associated with mitochondria. This was consistent with the quantitative proteomic analysis that showed dominance of proteins promoting cell growth and intercellular matrix development in the TME of CCII group. The interferon-α and γ response appeared the most activated pathways in many cell populations of the CCI patients. Several collagens, such as COL12A1, COL5A1, COL4A1 and COL4A2, were found significantly upregulated in the CCII group, suggesting their roles for diagnosing CC progression. A novel transcript AC244205.1 was detected as the most upregulated gene in CCII patients, and its possible mechanistic role CC may be investigated further. Conclusions Our study provides important resources for decoding the progression of CC and set the foundation for developing novel approaches for diagnosing CC and tackling the immunosuppressive TME.

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Single-Cell RNA Sequencing Reveals Multiple Pathways and the Tumor Microenvironment Could Lead to Chemotherapy Resistance in Cervical Cancer

Cited by 9 publications

References 75 publications

Dissecting the Single-Cell Transcriptome Network of Immune Environment Underlying Cervical Premalignant Lesion, Cervical Cancer and Metastatic Lymph Nodes

Dissecting the Single-Cell Transcriptome Network of Immune Environment Underlying Cervical Premalignant Lesion, Cervical Cancer and Metastatic Lymph Nodes

Single-Cell Sequencing Yields Insights in the Evolution of Foot-and-Mouth Disease Virus Persistent Infection

Single-cell transcriptomics and deep tissue proteomics reveal distinct tumour microenvironment present in stage-I and II cervical cancer

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