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Breast Cancer Stem Cells Regulated Metabolism Remodeling of Bulk Tumor Cells Drives Immune Evasion

ABSTRACT: Reprogramming of energy metabolism plays pivotal roles in cancer progression and immune surveillance. Here, we demonstrated that breast cancer cells showed positive feedback enhanced aerobic glycolysis in hypoxia condition. Further investigation suggested that breast cancer stem cells (BCSCs) induced by hypoxia stimulate aerobic glycolysis in bulk tumor cells. Cells cultured with hypoxic tumor cell- or BCSC-secretome exhibited similar gene expression patterns, with global remodeling of metabolism pathways, particularly glycolysis. BCSCs regulated glycolysis promoted breast cancer progression and evasion of immune surveillance. Screening of BCSC secretome identified MIF as a pivotal factor that potentiated glycolysis by increasing the expression of ALDOC. Breast cancer cell–intrinsic MIF depletion inhibited tumor progression and augmented intratumoral cytolytic CD8+ T cells and pro-inflammatory macrophages. Targeting MIF optimized immune checkpoint therapy of breast cancer in both syngeneic mouse models and humanized mouse model. Hence, this study delineates the contribution of BCSC regulated bulk tumor cell glycolysis in immune surveillance; and thereby proposes strategies to optimize immunotherapy in breast cancer.

ORGANISM(S): Homo

PROVIDER: GSE220616 | GEO | 2023/06/06

REPOSITORIES: GEO

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Breast Cancer Stem Cells Regulated Metabolism Remodeling of Bulk Tumor Drives Immune Evasion

Project description:Reprogramming of energy metabolism plays pivotal roles in cancer progression and immune surveillance. Here, we demonstrated that hypoxic cancer cell secretome and breast cancer stem cell (BCSC) secretome similarly promoted the global reprogramming of metabolic pathways, particularly glycolysis, in normoxic cancer cells. Screening of BCSC secretome identified MIF as a pivotal factor potentiating glycolysis via transcriptional activation of ALDOC expression by MYC. Targeting MIF attenuated glycolysis as well as impaired tumor growth and metastasis. Cell-intrinsic MIF depletion in breast cancer augmented intratumoral cytolytic CD8+ T cells and pro-inflammatory macrophages while decreased tumor-associated neutrophils. Targeting MIF improved anti-PD-L1 immune checkpoint therapy of triple-negative breast cancer cells. Hence, this study presented a paradigm of heterocellular metabolic communication in modulating tumor energy metabolism and immune surveillance, and thereby proposes strategies to ameliorate immunotherapy in breast cancer.

2024-01-31 | GSE235445 | GEO

Breast cancer stem cell-derived tumors escape from γδ T cell immunosurveillance in vivo by modulating γδ T cell ligands

Project description:Triple negative breast cancer (TNBC) lacks targeted therapy options. TNBC is enriched in breast cancer stem cells (BCSCs), which play a key role in metastasis, chemoresistance, relapse and mortality. γδ T cells hold great potential in immunotherapy against cancer, and might be an alternative to target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor sensing, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. We show that patient derived triple negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T cell immunotherapy. Mechanistically, we unraveled concerted differentiation and immune escape: xenografted BCSCs lost stemness, expression of γδ T cell ligands, adhesion molecules and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither pro-migratory engineered γδ T cells, nor anti-PD 1 checkpoint blockade significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells, and could be pharmacologically reverted by Zoledronate or IFN-α treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.

2023-07-20 | PXD039463 | Pride

miR-600 acts as a bimodal switcher that regulates breast cancer stem cell fate through WNT signaling

Project description:Breast cancer stem cells (bCSCs) have been implicated in tumor progression and therapeutic resistance; however, the molecular mechanisms that define bCSC-state are unclear. We have performed concurrent human miRNome-wide gain- and loss-of-function screens to identify switcher miRNAs controling the choice between bCSC self-renewal and differentiation. These analysis enlightened miR-600 whose silencing resulted in bCSC expansion. Mechanistically, miR-600 targets the stearoyl desaturase 1 (SCD1), an enzyme required to produce active, lipid-modified WNT proteins. To explore further miR-600 interactions and WNT-pathway, SUM159 cell line constructions were made and FACS-sorted to select the bCSCs. We compared gene expression profiles from native, miR-600 'over-expressed', miR-600'knock-down' and siSCD1 bCSCs. We showed that in the absence of miR-600, WNT signaling is maintained active and promotes self-renewal, whereas overexpression of miR-600 inhibits the production of active WNT proteins and promotes bCSC differentiation. These findings highlight a miR-600-centered signaling network that governs bCSC-fate decision and influences tumor progression.

2020-08-25 | E-MTAB-5393 | biostudies-arrayexpress

Expression data of ALDH+ breast cancer cells

Project description:It has been suggested that breast cancers are driven and maintained by a cellular subpopulation with stem cell properties. These breast cancer stem cells (BCSCs) mediate metastasis and by virtue of their resistance to radiation and chemotherapy, contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSC populations. Based on established breast cancer cell lines, as well as primary tumor samples and xenografts, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition, EMT) and epithelial-like (mesenchymal-epithelial transition, MET) states characterized by expression of distinct markers, proliferative capacity and invasive characteristics. The gene expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across the different molecular subtypes of breast cancer and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs allowing them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination and growth at metastatic sites. Breast cancer cells from patient were sorted using flow cytometry to select for cells that were ALDH+. Gene expression profiles of these cells were compared with profiles of ALDH- cells.

2013-11-14 | E-GEOD-52327 | biostudies-arrayexpress

Expression data of CD24-CD44+ and ALDH+ cells

Project description:It has been suggested that breast cancers are driven and maintained by a cellular subpopulation with stem cell properties. These breast cancer stem cells (BCSCs) mediate metastasis and by virtue of their resistance to radiation and chemotherapy, contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSC populations. Based on established breast cancer cell lines, as well as primary tumor xenografts, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition, EMT) and epithelial-like (mesenchymal-epithelial transition, MET) states characterized by expression of distinct markers, proliferative capacity and invasive characteristics. The gene expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across the different molecular subtypes of breast cancer and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs allowing them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination and growth at metastatic sites. Breast cancer cell lines, primary xenografts and normal breast cells from patient were sorted using flow cytometry to select for cells that were CD24-,CD44+ and ALDH+. Gene expression profiles of CD24-CD44+ cells were compared with non-CD24-CD44+ cells. Gene expression profiles of ALDH+ cells were compared with ALDH- cells.

2013-11-13 | E-GEOD-52262 | biostudies-arrayexpress

Paracrine Secretion of IL8 by Breast Cancer Stem Cells Promotes Therapeutic Resistance and Metastasis

Project description:Breast cancer stem cells (CSCs) play pivotal roles in cancer therapeutic failure and metastasis. However, it remains indeterminate how CSCs determine the progression of the bulk cancer cell population. Using a co-culture system in vitro and a co-implantation system in vivo, it is demonstrated herein that the breast cancer stem cell (BCSC) secretome rendered the bulk cancer cell population resistant to anti-estrogen and CDK4/6 inhibitor therapy; as well as increased the metastatic burden attributable to bulk cancer cells. Screening of BCSC secretome identified IL8 as a pivotal factor that potentiated ERα activity, endowed tamoxifen resistance and enhanced metastatic burden by regulation of bulk cancer cell behavior. Pharmacological inhibition of IL8 increased the efficacy of fulvestrant and/or palbociclib by reversing tamoxifen resistance and abrogated metastatic burden. Hence, this study has delineated the mechanism by which BCSCs determine the therapeutic response and metastatic of bulk cancer cells; and thereby suggests novel therapeutic strategies to ameliorate breast cancer outcomes.

2022-12-30 | GSE220295 | GEO

Transcriptomic but not genomic variability confers phenotype of breast cancer stem cells

Project description:Background: Breast cancer stem cells (BCSCs) are considered responsible for cancer relapse and drug-resistance. Understanding the identity of BCSCs may open new avenues in breast cancer therapy. Although several discoveries have been made on BCSCs characterization, the factors critical to BCSCs is largely unclear. This study was aimed to determine whether genomic mutation contributes to the acquisition of cancer stem-like phenotype, and to investigate the genetic and transcriptional features of BCSCs. Methods: We detected the potential mutation hotspot regions by using whole genome sequencing on parental cancer cells and derived serial-generation spheroids in increasing order of BCSC frequency, and then performed target deep DNA sequencing in the level of bulk-cell and single-cell. To identify the transcriptional program associated with BCSCs, bulk-cell and single-cell RNA sequencing were performed. Results: By analyzing whole genome sequencing of bulk cells, potential BCSCs associated mutation hotspot regions were detected. Validation by target deep sequencing, in both bulk-cell and single-cell levels, revealed no genetic changes specifically associated with BCSC phenotype. Moreover, single-cell RNA sequencing showed that cancer cells display profound transcriptional variability at the single-cell level that predicts BCSC features. Notably, this transcriptomic variability is enriched in transcription of a number of genes, revealed as BCSC markers. Individuals with breast cancer in a high-risk recurrence group exhibited higher expression of these transcriptomic variabilities, highlighting their clinical significance. Conclusions: Transcriptional variability, not genetic mutations, distinguish BCSCs from non-BCSCs. The identified BCSCs markers can become novel targets for BCSCs.

2018-10-12 | GSE116180 | GEO

Expression data of CD24-CD44+ and ALDH+ cells

Project description:It has been suggested that breast cancers are driven and maintained by a cellular subpopulation with stem cell properties. These breast cancer stem cells (BCSCs) mediate metastasis and by virtue of their resistance to radiation and chemotherapy, contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSC populations. Based on established breast cancer cell lines, as well as primary tumor xenografts, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition, EMT) and epithelial-like (mesenchymal-epithelial transition, MET) states characterized by expression of distinct markers, proliferative capacity and invasive characteristics. The gene expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across the different molecular subtypes of breast cancer and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs allowing them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination and growth at metastatic sites.

2013-11-13 | GSE52262 | GEO

Expression data of ALDH+ breast cancer cells

2013-11-14 | GSE52327 | GEO

Leptin as a Mediator of Tumor-Stromal Interactions Promotes Breast Cancer Stem Cell Activity

Project description:Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and resistance to anticancer therapies. These cells rely for their properties on complex interactions with the tumor microenvironment through networks of cytokines and growth factors. In this study, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using breast cancer cell lines and patient-derived samples. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology in mammosphere cells treated with stromal cell-CM and leptin.

2015-12-17 | E-MTAB-3641 | biostudies-arrayexpress

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