Therapy-induced self-renewal of CD133hi cells regulates escape from tumor dormancy and endocrine-resistant metastatic luminal breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69280 | GEO | 2016/02/09
SECONDARY ACCESSION(S): PRJNA285078
REPOSITORIES: GEO
Similar Datasets
Project description:HT induces an OXPHOS metabolic editing of ER+ breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133hi/ERlo cells mediating metastatic progression, which is sensitive to dual targeted therapy In this study, we demonstrated that CD133hi cells can mediate HT resistance and metastatic progression. Using human luminal breast cancer cell lines we have developed an in vivo model of spontaneous metastatic disease recapitulating what is observed in patients. Combining in vivo and in vitro studies we identified a de-novo cancer stem cell population (CSCs) âCD133hi/ERlo/Notch3hi/IL6hiâ, which are generated from non-CSCs via the sustained suppression of ER activity. We provide evidence that an ER-IL6-IL6R-CD133 loop is a mechanism mediating HT-resistance. Cancer cells were isolated from primary tumor and metastases, labeled with anti-CD133/CD44 conjugated antibodies and FACS sorted (gated on GFP, cancer cells).For microarray gene expression profiling and real time PCR (QPCR), we extracted RNA using Trizol (Invitrogen) from FACS sorted tumour derived cells. RNA concentration was determined with a NanoDrop 2000. The samples were prepared according to standard protocols and hybridized them on Affymetrix HG-U133 A 2.0 microarrays. We normalized the data using Microarray Suite 5.0. Differentially expressed genes between groups were identified with fold-change and t-test cut-offs.
2016-02-09 | E-GEOD-69280 | biostudies-arrayexpress
Project description:Although the estrogen receptor (ER) positive variant of breast cancer is touted as the most indolent and favorable, the majority of breast cancer deaths are in fact from this subtype. There are several features of this category of breast cancers that likely account for this outcome. The first is that metastatic relapse can occur many years after initial diagnosis of primary disease. The second is that once the cancer cells awaken into full-blown metastatic disease, they are largely resistant to ER-directed therapies (i.e. hormonal therapy, HT). The third is that when metastases do occur, they are invariably in many locations. This observation suggests that these dormant/sleeping metastatic cells are “globally” awakened as if by a “systemic” infection. We suggest that these three processes be not only linked, but underlie the lethal features of metastatic disease. We hypothesized that mtDNA is necessary for the escape from therapy induced tumor dormancy of luminal breast cancer cells
2017-07-01 | GSE84104 | GEO
Project description:Patients with estrogen-receptor-positive (ER+) breast cancer, the most common subtype, remain at risk for lethal metastatic disease years after diagnosis. Recurrence arises partly because tumor cells in bone marrow become resistant to estrogen-targeted therapy. Here, we utilized a co-culture model of bone marrow mesenchymal stem cells (MSCs) and ER+ breast cancer cells to recapitulate interactions of cancer cells in bone marrow niches. ER+ breast cancer cells in direct contact with MSCs acquire cancer stem-like (CSC) phenotypes with increased resistance to standard antiestrogenic drugs. We confirmed that co-culture with MSCs increased labile iron in breast cancer cells, a phenotype associated with CSCs and disease progression. Clinically approved iron chelators and in-house lysosomal iron-targeting compounds restored sensitivity to antiestrogenic therapy. These findings establish iron modulation as a mechanism to reverse MSC-induced drug resistance and suggest iron modulation in combination with estrogen-targeted therapy as a promising, translatable strategy to treat ER+ breast cancer.
2022-07-21 | GSE196312 | GEO
Project description:Interleukin 6 (IL6) signaling has been associated with an aggressive and metastatic phenotype in multiple solid tumors including breast cancer, but its mechanism of action in mediating tumor progression and treatment response is not clear. By exploiting a clinically relevant intraductal xenograft model of estrogen receptor positive (ER+) breast cancer, we demonstrate that IL6 increases both primary tumor growth and distant metastases. By integrating pre-clinical models and clinical specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates IL6-induced activation of a metastatic gene program from enhancer-elements shared with ER and its pioneer factor FOXA1. Although IL6 activated STAT3 and ER/FOXA1 share cis-regulatory regions, STAT3 drives transcription independent of ER and FOXA1 function, and the IL6/STAT3 gene program is not influenced by ER-targeted therapies, decoupling these two important pathways. This demonstrates that ER/FOXA1 and IL6/STAT3 are two parallel, but independent actionable pathways controlling breast cancer progression.
2021-09-08 | PXD012980 | Pride
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:Interleukin 6 (IL6) signaling has been associated with an aggressive and metastatic phenotype in multiple solid tumors including breast cancer, but its mechanism of action in mediating tumor progression and treatment response is not clear. By exploiting a clinically relevant intraductal xenograft model of estrogen receptor a positive (ER+) breast cancer, we demonstrate that IL6 increases both primary tumor growth and distant metastases. In pre-clinical models and clinical specimens, signal transducer and activator of transcription 3 (STAT3) mediates IL6-induced activation of a metastatic gene program from enhancers shared with ER and its pioneer factor FOXA1. However, STAT3 drives transcription independent of ER and FOXA1 function from these enhancers, and the IL6/STAT3 pathway is therefore resistant to ER-targeted therapies, decoupling these two important oncogenic pathways. This demonstrates that ER/FOXA1 and IL6/STAT3 are two parallel, but functionally independent and actionable pathways controlling breast cancer progression.
2020-07-17 | GSE126003 | GEO
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
Project description:Interleukin 6 (IL6) signaling has been associated with an aggressive and metastatic phenotype in multiple solid tumors including breast cancer, but its mechanism of action in mediating tumor progression and treatment response is not clear. By exploiting a clinically relevant intraductal xenograft model of estrogen receptor positive (ER+) breast cancer, we demonstrate that IL6 increases both primary tumor growth and distant metastases. By integrating pre-clinical models and clinical specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates IL6-induced activation of a metastatic gene program from enhancer-elements shared with ER and its pioneer factor FOXA1. Although IL6 activated STAT3 and ER/FOXA1 share cis-regulatory regions, STAT3 drives transcription independent of ER and FOXA1 function, and the IL6/STAT3 gene program is not influenced by ER-targeted therapies, decoupling these two important pathways. This demonstrates that ER/FOXA1 and IL6/STAT3 are two parallel, but independent actionable pathways controlling breast cancer progression.
2020-07-17 | GSE126004 | GEO
Project description:Interleukin 6 (IL6) signaling has been associated with an aggressive and metastatic phenotype in multiple solid tumors including breast cancer, but its mechanism of action in mediating tumor progression and treatment response is not clear. By exploiting a clinically relevant intraductal xenograft model of estrogen receptor positive (ER+) breast cancer, we demonstrate that IL6 increases both primary tumor growth and distant metastases. By integrating pre-clinical models and clinical specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates IL6-induced activation of a metastatic gene program from enhancer-elements shared with ER and its pioneer factor FOXA1. Although IL6 activated STAT3 and ER/FOXA1 share cis-regulatory regions, STAT3 drives transcription independent of ER and FOXA1 function, and the IL6/STAT3 gene program is not influenced by ER-targeted therapies, decoupling these two important pathways. This demonstrates that ER/FOXA1 and IL6/STAT3 are two parallel, but independent actionable pathways controlling breast cancer progression.
2020-07-17 | GSE150131 | GEO
Project description:Hormonal therapy (HT) inhibits the growth of hormone receptor-positive (HR+) breast (BrCa) and prostate (PrCa) cancers. HT resistance frequently develops within the complex metastatic microenvironment of the host-organ (often the bone), a setting poorly recapitulated in two-dimensional (2D) culture systems. To address this limitation, we cultured HR+ BrCa/PrCa spheroids and patient-derived organoids in 3D extracellular matrices (ECM) alone or together with bone marrow stromal cells (BMSCs). In 3D monocultures, antiestrogens/antiandrogens induced anoikis by abrogating the anchorage-independent growth of HR+ cancer cells but had only modest effect against tumor cells residing in the ECM niche. In contrast, BMSCs induced hormone-independent growth of BrCa/PrCa spheroids and restored lumen filling in the presence of HR-targeting agents. Molecular and functional characterization of the BMSC-induced hormone-independence and HT resistance in anchorage-independent cells revealed distinct, context-dependent, mechanisms. Cocultures of ZR75-1 and LNCaP with BMSCs exhibited paracrine IL-6-induced HT resistance via attenuation of HR protein expression, which was reversed by inhibition of IL-6 or JAK signaling. This paracrine IL-6/JAK/STAT3-mediated HT resistance was also confirmed in patient-derived organoids cocultured with BMSCs. Distinctly, MCF7 and T47D spheroids retained ER protein expression in cocultures, but also acquired redundant compensatory signals enabling anchorage independence via ERK and PI3K bypass cascades activated in non-IL-6-dependent manner. In summary, the acquisition of anchorage-independent growth in HR+ tumors is abrogated by HR blockade, but can be restored in the metastatic microenvironment through pleiotropic hormone-independent mechanisms. Combined analysis of tumor and microenvironmental biomarkers in metastatic biopsies of HT-resistant patients can help the refinement of treatment approaches.
2021-01-31 | GSE152312 | GEO