Therapy-induced self-renewal of CD133hi cells regulates escape from tumor dormancy and endocrine-resistant metastatic luminal breast cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69280 | GEO | 2016/02/09
SECONDARY ACCESSION(S): PRJNA285078
REPOSITORIES: GEO
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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: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:Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. Using a co-culture model, we performed an integrated transcriptomic and proteomic analysis of processes induced in ER+ breast cancer cells by close contact with MSCs, but not merely by conditioned media. Computational approaches identified a 52-protein/mRNA ‘signature’ which stratified patients at high risk for relapse, and implicated long-distance intercellular transport via tunneling nanotubes (TNTs) as a means for their ‘acquisition’ by the tumor cell from MSCs. Bioinformatic analyses helped prioritize one gene/protein, CCDC88A/GIV, a multi-functional adapter protein known to drive metastasis. MSCs upregulated GIV in ER+ breast cancer cells through connexin 43-mediated intercellular transport. Stable expression of GIV conferred resistance to clinical anti-estrogen drugs, enhanced tumor dissemination, and recapitulated the 52-gene signature. These data establish a new multi-omic resource for the regulation of breast cancer by MSCs via intercellular transport and validate as proof-of-concept how one transported protein, GIV, orchestrates aggressive disease states.
2024-07-02 | PXD039860 | Pride
Project description:Breast cancer patients with estrogen receptor positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cells display “stem like” properties (CSCs), which may be regulated by the immune system. Although many studies have examined tumor cell intrinsic characteristics of dormancy, the role of the immune system in controlling dormancy and its escape is not well understood. This scientific gap is due, in part, to a lack of immunocompetent mouse models of breast cancer dormancy with many studies involving human xenografts in immunodeficient mice. To overcome this limitation, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. We find that PyMT, Met-1 and D2.0R cell lines contain CSCs that display both short- and long-term metastatic dormancy in vivo, which is dependent on the host immune system. Natural killer cells were key for the metastatic dormancy phenotype observed for D2.0R and the role of NK cells in regulating CSCs was further investigated. Quiescent D2.0R CSC are resistant to NK cytotoxicity, while proliferative D2.0R CSC were sensitive to NK cytotoxicity both in vitro and in vivo. This resistance was mediated, in part, by the expression of Bach1 and Sox2 transcription factors. NK killing was enhanced by the STING agonist MSA-2. Collectively, our findings demonstrate the important role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon.
2024-05-15 | GSE267583 | 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: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.
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Project description:Metastatic tumors remain lethal due to primary/acquired resistance to therapy or cancer stem cell (CSC)-mediated repopulation. We show that a fasting-mimicking diet (FMD) activates starvation escape pathways in triple negative breast cancer (TNBC) cells, which can be identified and targeted by drugs. In CSCs, FMD cycles lower glucose-dependent protein kinase A signaling and stemness markers to reduce cell number and increase mouse survival. Accordingly, metastatic TNBC patients with lower glycemia survive longer than those with higher baseline glycemia. By contrast, in differentiated cancer cells, FMD cycles activate PI3K-AKT, mTOR and CDK4/6 as survival/growth pathways, which can be targeted by drugs to promote tumor regression. FMD cycles also prevent hyperglycemia and other toxicities caused by these drugs. These data indicate that FMD has wide and differential effects on normal, cancer and cancer stem cells, allowing the rapid identification and targeting of starvation escape pathways and providing a method potentially applicable to many malignancies.
2022-01-26 | GSE184452 | GEO
Project description:Oncogenic cell-surface membrane proteins contribute to the phenotypic and functional characteristics of cancer stem cells (CSCs). We quantitatively analyzed cell-surface membrane proteins that are in close proximity to CD147 in CSCs using proximity-labeling proteomic approach. Moreover, we compared CSCs to non-CSCs to identify CSC-specific cell-surface membrane proteins that are the nearest neighbors of CD147 and revealed that lateral interaction between CD147 and CD276 (B7H3) concealed within the lipid raft microdomain in CSCs confers resistance to docetaxel, known to treat many types of cancer patients including metastatic breast cancer. Furthermore, we found that co-expression of CD147 and CD276 in patients with HER2+ breast cancer who received chemotherapy had poor disease-free survival (DFS) and Overall survival (OS) rates (p = 0.04 and 0.08, respectively). Subsequent immunohistochemical analysis indicated that co-expression of CD147 and CD276 may be associated with poor response to chemotherapy in an independent HER2+ BC cohort. Altogether, our study suggests that the lateral interaction between CD147 and its proximal partners, such as CD276, may be related to a poor prognostic factor in BC and a predictive marker for the critical phenotypic determinant of breast cancer stemness.
2023-10-24 | PXD036909 | Pride
Project description:Estrogen receptor positive (ER+) breast cancers that develop resistance to therapies that target the ER are the most common cause of breast cancer death. Beyond mutations in ER, which occur in 25-30% of patients treated with aromatase inhibitors (AIs), our understanding of clinical mechanisms of resistance to ER-directed therapies remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to ER-directed agents, including AIs, tamoxifen, and fulvestrant. Examination of treatment-naïve primary tumors in five patients revealed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. These mutations were mutually exclusive with ER mutations, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that these mutations conferred estrogen independence. In addition, and in contrast to ER mutations, these mutations resulted in resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib, highlighting an effective treatment strategy in these patients.
2018-10-19 | GSE121411 | GEO