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Using single cell RNA-seq to assess heterogeneous subpopulations and optimize therapeutic strategy in triple-negative breast cancer cells

ABSTRACT: Purpose: Triple Negative Breast Cancer (TNBC) is a particularly aggressive form of breast cancer with high intertumoral and intratumoral heterogeneity. Our overall goal in this study is to investigate the heterogeneity of TNBC, and develop effective combination therapy. Methods: We applied HCC1143 cell line as a representative of aggressive TNBC and performed single cell RNA-seq with 10x genomics platform for cells before and after paclitaxel treatment. Different cell subpopulations were identified with Seurat, and the relationship between different subpoulations were investigated with scEpath. Results: Different subpopulations were detected in TNBC cell populations. Targetable genes were identified and some of them were validated with drug.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139129 | GEO | 2022/10/18

REPOSITORIES: GEO

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Comprehensive proteomic characterization reveals subclass-specific molecular aberrations within triple-negative breast cancer

Project description:Triple-negative breast cancer (TNBC) is regarded as the most aggressive subtype of breast cancer lacking targeted therapies. This is attributed to its high heterogeneity that complicates elucidation of its molecular aberrations. Here, we report identification of specific proteome expression profiles pertaining to two TNBC subclasses, basal A and basal B, through in-depth proteomics analysis of breast cancer cells. We observed that kinases and proteases displayed unique expression patterns within the subclasses, similar to whole proteome clusters. Systematic analyses of protein-protein interaction and co-regulation networks of these kinases and proteases unraveled dysregulated pathways and plausible targets for each TNBC subclass. Among these, we identified kinases AXL, PEAK1 and TGFBR2, and proteases FAP, UCHL1 and MMP2/14, as specific targets for basal B subclass, which represents the more aggressive TNBC cell lines. Our study thus highlights intricate mechanisms and distinct targets within TNBC, and emphasizes that these have to be exploited in a subclass-specific manner rather than a one-for-all TNBC therapy.

2020-03-03 | PXD017025 | Pride

TCOF1 DRIVES STEMNESS OF TRIPLE-NEGATIVE BREAST CANCER THROUGH KIT

Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis. The high malignancy of TNBC is contributed by its heterogeneity and enrichment of cancer stem cells. By performing multiomic profiling, we recently uncovered super-enhancer heterogeneity between breast cancer subtypes. Here, we identify TCOF1 as a novel super-enhancer-regulated gene that promotes TNBC growth and stemness. TCOF1, which plays a critical role in craniofacial development, is frequently upregulated in TNBC and its elevated expression correlates with shorter overall survival. Whereas TCOF1 depletion has potent effects on the growth and stemness of basal-like TNBC, it has no effect on mesenchymal-like cells, highlighting the distinct molecular dependency in different subgroups of TNBC. Whole genome RNA sequencing uncovers several stem cell molecules regulated by TCOF1. We further demonstrate that the upregulation of KIT by TCOF1 mediates TNBC stemness. These findings provide a rationale for developing therapeutics targeting TCOF1 in basal-like TNBC.

2021-11-02 | GSE168835 | GEO

Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq [RNA-Seq]

Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by extensive intratumoral heterogeneity. To investigate the underlying biology, we conduct single-cell RNA- sequencing (scRNA-seq) of >1500 cells from six primary TNBC. Intercellular heterogeneity of gene expression programs within each tumor was variable and largely correlated with clonality of inferred genomic copy number changes, suggesting that genotype drives the gene expression phenotype of individual subpopulations. Clustering of gene expression profiles identified distinct subgroups of malignant cells shared by multiple tumors, including a single subpopulation associated with multiple signatures of treatment resistance and metastasis, and characterized functionally by activation of glycosphingolipid metabolism and associated innate immunity pathways. A novel signature defining this subpopulation was predictive of long-term outcomes for TNBC patients in a large patient cohort. Collectively, this analysis reveals the functional heterogeneity and its association with genomic evolution in TNBC, and uncovers unanticipated biological principles dictating poor outcomes in this disease.

2018-08-11 | GSE118389 | GEO

Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq [WES]

Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by extensive intratumoral heterogeneity. To investigate the underlying biology, we conduct single-cell RNA- sequencing (scRNA-seq) of >1500 cells from six primary TNBC, together with whole exome sequencing (WES) for four of the tumors. Intercellular heterogeneity of gene expression programs within each tumor was variable and largely correlated with clonality of inferred genomic copy number changes, suggesting that genotype drives the gene expression phenotype of individual subpopulations. Clustering of gene expression profiles identified distinct subgroups of malignant cells shared by multiple tumors, including a single subpopulation associated with multiple signatures of treatment resistance and metastasis, and characterized functionally by activation of glycosphingolipid metabolism and associated innate immunity pathways. A novel signature defining this subpopulation was predictive of long-term outcomes for TNBC patients in a large patient cohort. Collectively, this analysis reveals the functional heterogeneity and its association with genomic evolution in TNBC, and uncovers unanticipated biological principles dictating poor outcomes in this disease.

2018-08-11 | GSE118303 | GEO

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Project description:Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by extensive intratumoral heterogeneity, high metastasis and chemoresistance, leading to poor clinical outcomes. Despite progress, the mechanistic basis of these aggressive behaviours remains poorly understood. Using single-cell and spatial transcriptome analysis, here we discovered basal epithelial subpopulations located within the stroma that exhibit chemoresistance characteristics. The subpopulations are defined by distinct signature genes that show a frequent gain in copy number and exhibit an activated epithelial-to-mesenchymal transition program. A subset of these genes can accurately predict chemotherapy response and are associated with poor prognosis. Interestingly, among these genes, elevated ITGB1 participates in enhancing intercellular signaling while ACTN1 confers a survival advantage to foster chemoresistance. Furthermore, by subjecting the transcriptional signatures to drug repurposing analysis we find that chemoresistant tumors may benefit from distinct inhibitors in treatment naïve versus post-NAC patients. These findings shed light on the mechanistic basis of chemoresistance while providing the best-in-class biomarker to predict chemotherapy response and alternate therapeutic avenues for improved management of TNBC patients resistant to chemotherapy.

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Project description:Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression. Kinase enrichment proteomic analysis was performed using HCC1143 breast cancer cells treated with a control siRNA pool or a pool targeting SOX4 in biological triplicate to evaluate the effects on the functional kinome.

2021-03-03 | PXD022596 | Pride

Differential analysis of nucleolar proteomics in triple negative breast cancer

Project description:Breast cancer is one of the most common cancers in women. Of the different subtypes of breast cancer, the triple negative breast cancer subtype of breast cancer is the most aggressive. A proteomic screen of nucleolar content across breast cancer subtypes found that triple negative breast cancer cell lines have a distinct nucleolar proteome signature in comparison to non-TNBC breast cancer cell lines.

2021-03-05 | PXD021201 | Pride

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Project description:We performed single-cell combinatorial indexing ATAC-seq on the basal-like TNBC cell line HCC1143 under MEK, PI3K, BET and combination treatments as well as DMSO controls

2019-02-08 | GSE126261 | GEO

High accuracy gene expression profiling of sorted cell subpopulations from breast cancer PDX model tissue

Project description:Data sets from 2 experiments using PDX derived human TNBC tissue to compare gene expression between cell subpopulations with distinct marker profiles. The first experiment describes comparison of CD184hi vs. CD184lo population, the second experiment (with a different mouse model) compares CD49f lo vs. CD49fhi as well as CD133lo vs. CD133hi. Each subpopulation shows distinct expression patterns suggestive of distinct function within breast cancer tissue.

2020-08-20 | E-MTAB-9428 | biostudies-arrayexpress

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