Dataset Information

Single-Cell Mobility Analysis of Metastatic Breast Cancer Cells.

ABSTRACT: Efforts have been taken to enhance the study of single-cells, however, the task remains challenging because most previous investigations cannot exclude the interactions between single cells or separately retrieved cells with specificity for further analyses. Here, a single-cell mobility analysis platform (SCM-Chip) is developed that can not only real-time monitor single-cell migration in independent niches but can also selectively recover target cells one by one. The design of each channel with a single-cell capture unit and an outlet enables the system to place single cells in different isolated niches with fluidic capture and to respectively collect target cells based on mobilities. SCM-Chip characterization of breast cancer cells reveals the presence of high- and low-migratory populations. Whole-cell transcriptome analysis establishes that monocyte chemotactic protein induced protein 1 (MCPIP1) is related with cell mobility; cells with a high expression of MCPIP1 exhibit low mobility in vitro and metastasis in vivo. The SCM platform provides a generic tool for accurate single-cell isolation and differentiation that can be readily adapted for the study of cancer and drug development.

SUBMITTER: Zhuang J

PROVIDER: S-EPMC6299679 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Single-Cell Mobility Analysis of Metastatic Breast Cancer Cells.

Zhuang Jialang J Wu Yongjian Y Chen Liang L Liang Siping S Wu Minhao M Zhou Ledu L Fan Chunhai C Zhang Yuanqing Y

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20181031 12

Efforts have been taken to enhance the study of single-cells, however, the task remains challenging because most previous investigations cannot exclude the interactions between single cells or separately retrieved cells with specificity for further analyses. Here, a single-cell mobility analysis platform (SCM-Chip) is developed that can not only real-time monitor single-cell migration in independent niches but can also selectively recover target cells one by one. The design of each channel with ...[more]

PMID: 30581709

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Project description:Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease.

Project description:BackgroundWe previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, p = 0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP).MethodsThe original trial randomized metastatic breast cancer patients to either 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5 Gy given in 3 doses of 7.5 Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression.ResultsAt baseline, a significantly higher level of expression (p < 0.05) of PD-L1 was identified in patient monocytes compared to HD. TCR modulation revealed dysfunction of circulating T-cells in patient baseline samples as compared to HD, and this was more pronounced in PD-1+ cells. Treatment with radiotherapy and fresolimumab did not resolve this dyfunctional signaling. However, in vitro PD-1 blockade enhanced TCR signaling in patient PD-1+ T cells and not in PD-1- T cells or in PD-1+ T cells from HD.ConclusionsFunctional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy.Trial registrationNCT01401062 .

Dataset Information

Single-Cell Mobility Analysis of Metastatic Breast Cancer Cells.

Publications

Single-Cell Mobility Analysis of Metastatic Breast Cancer Cells.

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