Paracrine Secretion of IL8 by Breast Cancer Stem Cells Promotes Therapeutic Resistance and Metastasis
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ABSTRACT:
ORGANISM(S): Homo
PROVIDER: GSE220295 | GEO | 2022/12/30
REPOSITORIES: GEO
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Project description:Breast cancers consist of heterogeneous cellular subpopulations that differ in molecular properties and functional attributes. Cancer cells display phenotypic equilibrium between the stem-like and differentiated states during neoplastic homeostasis. The mechanism and functional implications of the subpopulation equilibrium in cancer progression remain largely unknown. Herein, we report that BCSCs secretome conditioned bulk tumor cells developed resistance to anti-endocrine therapy both in vitro and in vivo. IL8 was significantly enriched in BCSCs secretome and blockade of IL8 signaling reversed the tamoxifen resistance induced by BCSCs. The enhanced Wnt/β-catenin signal simultaneously increased the secretion of IL8 in BCSCs, which leads to the seemingly contradictory behaviors of bulk tumor cells. Collectively, our study characterizes the paracrine effects and identifies key molecules secreted by BCSCs, which may become therapeutic vulnerabilities to overcome tamoxifen resistance.
2020-08-20 | GSE156454 | GEO
Project description: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.
2023-06-06 | GSE220616 | GEO
Project description:Self-renewal and differentiation are two epigenetic programs that regulate pluripotency of stem cells. During oncogenesis, dysregulation of these two programs leads to the development of cancer stem cells (CSCs). Here, we used a pan genomic promoter microarray to determine the DNA methylation portrait of breast cancer stem cells (bCSC) compared to non-bCSC
2015-01-01 | E-MTAB-2236 | biostudies-arrayexpress
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
Project description:We investigated the role of breast cancer stem-like cells (CSCs-like), isolated from primary tumor, in promoting bone metastases in a human-in-mice model. Luciferase-transduced CD44+CD24- breast CSCs-like were injected through subcutaneous (SC) and intracardiac (IC) route in nonobese/severe combined immunodeficient (NOD/SCID) mice carrying subcutaneous human bone implants. The implanted bone was viable, active and human neo-vascularization was present. By in vivo luciferase imaging, we monitored tumor growth and detected bone-localized breast CSCs-like, both after SC and IC injection. Bone metastatic lesions were histologically evident, and tumor cells expressed epithelial markers and vimentin. Bone metastatic cells isolated from bone implants showed a CD44-CD24+ phenotype and re-created tumors and bone metastases after injection in secondary mice. A “bone tropism” expression signature was found to distinguish bone-colonizing cells from parental CSCs-like and to persist at subsequent passages also in the absence of surrounding bone tissue. The bone tropism signature displayed significant enrichment in genes discriminating bone metastases of breast cancer from metastases at other organs. Our results demonstrate the ability of breast CSCs-like to promote bone metastasis and provide a CSCs-like bone tropism signature, with potential prognostic value. C10 breast cancer stem-like cells (CSCs-like) were derived as mammospheres from a lobular-infiltrating breast carcinoma (ER+, HER2-). Samples are organized in the following groups: (i) Breast CSCs-like (C10, duplicate); (ii) Luciferase-transduced CSCs-like (C10L, simplicate); (iii) Bone-isolated C10L metastatic cells (C10-bone, duplicate) and subsequently (iv) grown in vitro as spheroids (C10-CSC, simplicate) or (v) re-grown in subcutaneous implants (C10-SC, duplicate).
2013-11-30 | E-GEOD-36102 | biostudies-arrayexpress
Project description:Cancer stem cells (CSCs), a small subset of the tumor bulk with highly malignant properties, are deemed responsible for tumor initiation, growth, metastasis, and relapse. In order to reveal molecular markers and determinants of stemness properties, pancreatic CSCs were enriched in three-dimensional spheroid cultures of two highly metastatic pancreatic cancer cell lines (L3.6sl and L3.6pl) and compared to bulk tumor cells using differential proteomics (PTX). We identified about 400 putative target proteins with significantly different expression in pancreatic CSCs and bulk tumor cells. By combining the unbiased PTX with gene expression analysis using quantitative polymerase chain reaction (qPCR) we nominated the two calcium binding proteins S100A8 (MRP8) and S100A9 (MRP14), as well as galactin-3-binding protein LGALS3BP (MAC-2-BP) as putative determinants of pancreatic CSCs. In silico pathway analysis followed by candidate-based RNA interference mediated functional analysis revealed a critical role of S100A8, S100A9, and LGALS3BP as molecular determinants of CSC proliferation, migration and in vivo tumor initiation. Our study highlights the power of combining unbiased proteomics with focused gene expression and functional analyses for the identification of key regulators of CSCs, an approach that warrants further application to identify CSCs proteins amenable to drug targeting.
2020-06-25 | PXD018585 | Pride
Project description:AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment. The inhibitors were evaluated in breast cancer for both cytotoxicity and in metabolic stability assays across both murine and human breast cancer cell lines. Both AQP inhibitors also affected expression of other AQP transcripts and proteins, which demonstrates compensatory regulation between AQP family members. As a single agent, Auphen treatment in vivo extended overall survival but did not impact primary or metastatic tumor burden. However, Auphen treatment made cells more responsive to chemotherapy (doxorubicin) or endocrine treatment (tamoxifen, fulvestrant). In fact, treatment with Tamoxifen reduced the overall AQP7 protein expression. RNA-Seq of breast cancer cells treated with Auphen identified mitochondrial metabolism genes as impacted by Auphen and may contribute to reducing mammary tumor progression, lung metastasis, and increased therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we found that Auphen and tamoxifen cooperate to reduce breast cancer cell viability, which suggests that Auphen treatment makes the cells more susceptible to Tamoxifen. Together, this study highlights AQPs as therapeutic vulnerabilities of breast cancer metastasis that are promising and should be exploited. However, the pharmacologic results suggest additional chemical refinements and optimization of AQP inhibition are needed to make these AQP inhibitors appropriate to use for therapeutic benefit in overcoming endocrine therapy resistance.
2024-08-01 | GSE271926 | GEO
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
Project description:Approximately 70% of human breast cancers express estrogen receptor-α (ERα), providing a potential target for endocrine therapy. However, 30%–40% of patients with ER+ breast cancer still experience recurrence and metastasis, with a 5-year relative overall survival rate of 24%. In this study, we identified NAMPT, an important enzyme in nicotinamide adenine dinucleotide (NAD+) metabolism, to be increased in metastatic breast cancer (MBC) cells treated with Fulv. We tested whether blockade of NAD+ production via inhibition of nicotinamide phosphoribosyltransferase (NAMPT) synergizes with standard-of-care therapies for ER+ metastatic breast cancer in vitro and in vivo. A synergistic effect was not observed when KPT-9274 was combined with palbociclib or tamoxifen or when Fulv was combined with other metabolic inhibitors. We show that NAMPT inhibitor KPT-9274 and fulvestrant (Fulv) works synergistically to reduce metastatic tumor burden. RNA-sequencing analysis showed that NAMPT inhibition improved antiestrogenic activity of Fulv, and metabolomics analysis showed that NAMPT inhibition reduced the abundance of metabolites associated with several key tumor metabolic pathways. Targeting metabolic adaptations in endocrine-resistant metastatic breast cancer is a novel strategy, and alternative approaches aimed at improving the therapeutic response of metastatic ER+ tumors are needed. Our findings uncover the role of ERα–NAMPT cross-talk in metastatic breast cancer and the utility of NAMPT inhibition and antiestrogen combination therapy in reducing tumor burden and metastasis, potentially leading to new avenues of metastatic breast cancer treatment.
2023-05-27 | GSE233062 | GEO
Project description:Breast cancer is a curable disease if it is diagnosed at an early stage. However, only little options are left once the tumor is metastasized to distant organs, and more than 90% of breast cancer death is attributed to metastatic disease. The process of metastasis is highly complex and involves many steps for successful colonization of tumor cells at a target organ. According to the cancer stem cell (CSC) theory, which still remains a hypothesis, these metastatic cells must have stem cell-like capability for their self-renewal in addition to their invasive ability. Therefore, it has been predicted that a “metastatic stem cell”, which is distinct from a cancer stem cell, must exist in the primary tumor mass. To identify genes that are involved in metastasis of CSCs, we isolated CSC populations from a well-established model cell line of breast cancer, MDA-MB231, and that of highly metastatic variants, 231BoM-1833 and 231BrM-2a, using CD24, CD44 and EpCAM (ESA), which have been identified as surface markers for CSCs in breast cancers. Overall yield of CSCs from these cells ranged from 2% to 4%. We then performed global expression profile analysis for these CSCs using the Affymetrix Human Gene 1.0ST array. CSC populations (CD24-/CD44+/ESA+) from MDA-MB231, 231BoM-1833 and 231BrM-2a were isolated by magnetic-activated cell sorting (MACS) using specific antibodies to these surface markers. The total RNA was isolated from the CSC populations using the RNeasy RNA isolation kit (Qiagen). The RNA was then converted to cDNA and they were hybridized to the Human Gene 1.0ST chip (Affymetrix). The data was normalized using the RMA algorithm of the Expression Console software (Affymetrix). A comparison of transcriptional profiles was then performed in CSCs of highly metastatic cell lines (231BoM-1833 and 231BrM-2a) compared to the CSCs of MDA-MB-231.
2011-11-30 | E-GEOD-25976 | biostudies-arrayexpress