Single-cell transcriptomics reveal the heterogeneity and dynamic of cancer stem-like cells during breast tumor progression

AbstractBreast cancer stem-like cells (BCSCs) play vital roles in tumorigenesis and progression. However, the origin and dynamic changes of BCSCs are still to be elucidated. Using the breast cancer mouse model MMTV-PyMT, we constructed a single-cell atlas of 31,778 cells from four distinct stages of tumor progression (hyperplasia, adenoma/MIN, early carcinoma and late carcinoma), during which malignant transition occurs. We identified that the precise cell type of ERlow epithelial cell lineage gave rise to the tumors, and the differentiation of ERhigh epithelial cell lineage was blocked. Furthermore, we discovered a specific signature with a continuum of gene expression profiles along the tumor progression and significantly correlated with clinical outcomes, and we also found a stem-like cell cluster existed among ERlow epithelial cells. Further clustering on this stem-like cluster showed several sub-clusters indicating heterogeneity of stem-like epithelial cells. Moreover, we distinguished normal and cancer stem-like cells in this stem-like epithelial cell cluster and profiled the molecular portraits from normal stem-like cell to cancer stem-like cells during the malignant transition. Finally, we found the diverse immune cell infiltration displayed immunosuppressive characteristics along tumor progression. We also found the specific expression pattern of cytokines and their corresponding cytokine receptors in BCSCs and immune cells, suggesting the possible cross-talk between BCSCs and the immune cells. These data provide a useful resource for illuminating BCSC heterogeneity and the immune cell remodeling during breast tumor progression, and shed new light on transcriptomic dynamics during the progression at the single-cell level.

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P2-02-03: MAP3K3, Amplified in Human Breast Cancer, Promotes Breast Tumor Progression and Defines Poor Prognosis.

10.1158/0008-5472.sabcs11-p2-02-03 ◽

2011 ◽

Author(s):

J Dong

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Breast Tumor ◽

Human Breast Cancer ◽

Poor Prognosis ◽

Human Breast ◽

Breast Tumor Progression

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Squalene epoxidase expression is associated with breast tumor progression and with a poor prognosis in breast cancer

Oncology Letters ◽

10.3892/ol.2021.12520 ◽

2021 ◽

Vol 21 (4) ◽

Author(s):

Nah Kim ◽

Min Park ◽

Sun-Seog Kweon ◽

Namki Cho ◽

Ji Lee

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Breast Tumor ◽

Poor Prognosis ◽

Squalene Epoxidase ◽

Breast Tumor Progression

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A Single-Cell Immune Atlas of Triple Negative Breast Cancer Reveals Novel Immune Cell Subsets

10.1101/566968 ◽

2019 ◽

Cited By ~ 2

Author(s):

Si Qiu ◽

Ruoxi Hong ◽

Zhenkun Zhuang ◽

Yuan Li ◽

Linnan Zhu ◽

...

Keyword(s):

Breast Cancer ◽

Single Cell ◽

Immune Cells ◽

Triple Negative ◽

Immune Cell ◽

Cell Subset ◽

Valuable Resource ◽

Tcr Signaling ◽

Immune Cell Subsets ◽

Treatment Naïve

ABSTRACTTriple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, which recently attracts great interest for immune therapeutic development. In this context, in-depth understanding of TNBC immune landscape is highly demanded. Here we report single-cell RNA sequencing results of 9683 tumor-infiltrated immune cells isolated from 14 treatment naïve TNBC tumors, where 22 immune cell subsets, including T cells, macrophages, B cells, and DCs have been characterized. We identify a new T cell subset, CD8+CXCL8+ naïve T cell, which associates with poor survival. A novel immune cell subset comprised of TCR+ macrophages, is found to be widely distributed in TNBC tumors. Further analyses reveal an up-regulation of molecules associated with TCR signaling and cytotoxicity in these immune cells, indicating TCR signaling activation. Altogether, our study provides a valuable resource to understand the immune ecosystem of TNBC. The novel immune cell subsets reported herein might be functionally important in cancer immunity.SIGNIFICANCEThis work demonstrates a single-cell transcriptome atlas of immune cells in treatment naïve TNBC tumors, revealing novel immune cell subsets. This study provides a valuable resource to understand the immune ecosystem of TNBC, which will be helpful for the immunotherapeutic strategy design of TNBC.

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Skin-resident immune cells actively coordinate their distribution with epidermal cells during homeostasis

10.1101/2021.01.08.425932 ◽

2021 ◽

Author(s):

Sangbum Park ◽

Catherine Matte-Martone ◽

David G Gonzalez ◽

Elizabeth A Lathrop ◽

Dennis P May ◽

...

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Cell Density ◽

Immune Cells ◽

Immune Cell ◽

Basal Layer ◽

Cell Types ◽

Epidermal Cells ◽

Cell Junctions ◽

Epithelial Stem Cells

Our organs consist of multiple cell types that ensure proper architecture and function. How different cell types coexist and interact to maintain their homeostasis in vivo remain elusive. The skin epidermis comprises mostly epithelial cells, but also harbors Langerhans cells (LCs) and Dendritic Epidermal T cells (DETCs). In response to injury or infection, LCs and DETCs become activated and play critical immunological roles. During homeostasis, they coexist with epithelial cells in the basal layer of the epidermis. Whether, and how, distributions of LCs and DETCs are regulated during homeostasis is unclear. Here, we addressed this question by tracking LCs, DETCs and epithelial basal cells over time within the skin of live adult mice. We show that LCs and DETCs maintain their overall position despite continuous turnover of neighboring basal epithelial stem cells. Moreover, LCs and DETCs rapidly and maximally explore basal epithelial cell junctions through their dendritic extensions. Altering the epithelial cell density triggers corresponding changes in the immune cell density, but not vice versa, suggesting that epithelial cells determine immune tissue composition in the epidermis. Moreover, LCs and DETCs are organized in a tiling pattern that is actively maintained. When LCs or DETCs are ectopically removed, neighboring epidermal LCs or DETCs, respectively, move into the emptied spaces and re-establish the tiling pattern. Finally, LCs require the GTPase Rac1 to maintain their positional stability, density and tiling pattern. Overall, we discovered that epidermal cells regulate the density of immune cells during homeostasis, and that immune cells actively maintain a non-random spatial distribution, reminiscent of neuronal self-avoidance. We propose that these cellular mechanisms provide the epidermis with an optimal response to environmental insults.

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Single-cell protein analysis in support of biomarker evaluation for breast cancer immunotherapeutics.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.10 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 10-10

Author(s):

Vicki Plaks

Keyword(s):

Breast Cancer ◽

Single Cell ◽

Tumor Cells ◽

Immune Cells ◽

Mononuclear Cells ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Primary Breast Tumor ◽

Cell Protein ◽

Peripheral Blood Mononuclear

10 Background: Triple-negative breast cancer (TNBC) is being tested for PD-1/PD-L1 checkpoint inhibitors combination therapy. The relationship between tumor expression of PD-L1 and patient outcomes has been established using immunohistochemistry (IHC) biomarker assays across various malignancies. PD-L1 is expressed in tumor and immune cells within the tumors in TNBC, but only immune-cell PD-L1 is associated with response to anti-PD-L1 (atezolizumab) so differentiating tumor vs. immune PD-L1 expression is essential. The currently available IHC biomarker assays that relay on tissue biopsies struggle to provide clinically meaningful identification of responders vs. non-responders. Poor sensitivity and specificity is partially attributed to tumor heterogeneity that is not well-represented in these biopsies. In addition, PD-L1 expression may vary over time due to disease progression or treatment. Since tissue biopsy collection is often an invasive procedure, it is restricted. Needle biopsies can mitigate some of these issues as a minimally invasive method to probe multiple regions within several cancer lesions across several time points. MILO, a new single cell Western Blot (WB) technology allows quantitative measurements of multiple protein biomarkers within one cell in small samples. Methods: To evaluate the capability of MILO to differentiate between PD-L1 in immune and tumor cell populations, we interrogated BC cell lines as well as peripheral blood mononuclear cells (PBMCs) mixed in known ratios. We used MDA-MB-231 that shows high PD-L1 and low HER2 expression and BT-474, which shows the inverse expression profile for these biomarkers along with PBMCs as PD-L1+ immune cells. Primary breast tumor tissues are currently interrogated to establish utility in needle biopsies. Results: MILO demonstrated heterogeneity at the single-cell level of HER2 and PD-L1 expression in BC tumor cells and enabled differentiation between PD-L1 expression in immune vs. tumor cells using cell-specific markers and low cell numbers. Conclusions: MILO can improve patient selection and prediction of response to immune checkpoint inhibition by promoting the utility of needle biopsies to complement IHC of core biopsies.

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A Single-Cell Immune Atlas of Triple Negative Breast Cancer Reveals Novel Immune Cell Subsets

10.21203/rs.3.rs-64982/v1 ◽

2020 ◽

Author(s):

Si Qiu ◽

Ruoxi Hong ◽

Zhenkun Zhuang ◽

Linnan Zhu ◽

Yuan Li ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Single Cell ◽

Triple Negative Breast Cancer ◽

Immune Cells ◽

Triple Negative ◽

Immune Cell ◽

Breast Cancer Subtype ◽

Cell Subset ◽

Immune Cell Subsets

Abstract Background: Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, which recently attracts great interest for immune therapeutic development. In this context, in-depth understanding of TNBC immune landscape is highly demanded.Results: Here we report full-length single-cell RNA sequencing results of 9683 tumor-infiltrated immune cells isolated from 14 treatment naïve TNBC tumors, where 22 immune cell subsets, including T cells, macrophages, B cells, and DCs have been characterized. We identify a new T cell subset, CD8+CXCL8+ T cell, which associates with poor survival, and a subset of “pre-exhaustion” T cell cluster, which is predictive of favorable prognosis. A novel immune cell subset comprised of TCR+ macrophages, is found to be widely distributed in TNBC tumors. Further analyses reveal an up-regulation of molecules associated with TCR signaling and cytotoxicity in these immune cells.Conclusions: Altogether, our study provides a valuable resource to understand the immune ecosystem of TNBC. The novel immune cell subsets reported herein might be functionally important in cancer immunity. These data will be helpful for the immunotherapeutic strategy design of this disease.

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