M-Wnt claudin-low breast cancer model : metastatic derivatives
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE98703 | GEO | 2017/05/10
SECONDARY ACCESSION(S): PRJNA385955
REPOSITORIES: GEO
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Project description:Metastatic breast cancer is an extremely complex disease with limited treatment options due to the lack of information about the major characteristics of metastatic disease. There is an urgent need, therefore, to understand the changes in cellular complexity and dynamics that occur during metastatic progression. In the current study, we analyzed the cellular and molecular differences between primary tumors and paired lung metastases using a syngeneic p53-null mammary tumor model of basal-like breast cancer. Distinct subpopulations driven by the Wnt- and/or STAT3 signaling pathways were detected in vivo using a lentiviral Wnt- and STAT3 signaling reporter system. A significant increase in the overlapping populations driven by both the Wnt- and STAT3 signaling pathways was observed in the lung metastases as compared to the primary tumors. Furthermore, STAT3 signaling activity was markedly enhanced in the metastatic lesions relative to the primary tumors with minimal changes observed in Wnt reporter activity. An analysis of the unique molecular features of the lung metastases revealed a significant association with immune response signatures. Specifically, Foxp3 gene expression was markedly increased and elevated levels of Foxp3+ Treg cells were detected in close proximity to lung metastases. Collectively, these studies illustrate the importance of analyzing intratumoral heterogeneity, changes in population dynamics and the immune microenvironment during metastatic progression.
2019-08-06 | GSE132031 | GEO
Project description:Claudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS as well as regulators of EMT play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.
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Project description:Breast cancer stem cell (BCSC) line #1 and #4 were grown in either stem cell medium or medium favoring the differentiation. Cells were genetically labeled with fluorescent protein expression cassettes and xenotransplanted into immunocompromised mice, giving rise to tumors. Tumors were explanted, dissociated and kept in culture so as to isolate growing cells. Cells were then sorted for fluorescent protein expression and RNA was extracted. Breast cancer stem (BCSC) and differentiated (dBCCs) cells, grown in opportune conditions, were transfected with lentiviral vector encoding luciferase/enhanced green fluorescent protein (Luc/EGFP-BCSCs) or luciferase/red fluorescent protein (Luc/RFP-dBCCs) reporter genes and orthotopically injected in defined ratios (1:1) into immunocompromised mice. Primary tumor growth and the onset of distant metastases was then observed in time. Following primary and metastatic lesions resection, labeled dBCCs, BCSCs and metastatic derivatives, thereafter referred to as fat pad differentiated cells (FPD), fat pad stem cells (FPS) and metastases (Ms) respectively, were consequently isolated from through fluorescent-activated cell sorting and RNA extracted. 14 samples, with at least 2 biological replicates for each category
2013-09-15 | E-GEOD-48371 | biostudies-arrayexpress
Project description:Breast cancer stem cell (BCSC) line #1 and #4 were grown in either stem cell medium or medium favoring the differentiation. Cells were genetically labeled with fluorescent protein expression cassettes and xenotransplanted into immunocompromised mice, giving rise to tumors. Tumors were explanted, dissociated and kept in culture so as to isolate growing cells. Cells were then sorted for fluorescent protein expression and RNA was extracted. Breast cancer stem (BCSC) and differentiated (dBCCs) cells, grown in opportune conditions, were transfected with lentiviral vector encoding luciferase/enhanced green fluorescent protein (Luc/EGFP-BCSCs) or luciferase/red fluorescent protein (Luc/RFP-dBCCs) reporter genes and orthotopically injected in defined ratios (1:1) into immunocompromised mice. Primary tumor growth and the onset of distant metastases was then observed in time. Following primary and metastatic lesions resection, labeled dBCCs, BCSCs and metastatic derivatives, thereafter referred to as fat pad differentiated cells (FPD), fat pad stem cells (FPS) and metastases (Ms) respectively, were consequently isolated from through fluorescent-activated cell sorting and RNA extracted.
2013-09-15 | GSE48371 | GEO
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2009-02-11 | GSE14682 | GEO
Project description:Background: Metastases to the brain from breast cancer have a high mortality. Basal-like and HER2 positive breast cancers appear to have a high propensity to spread to the brain. The mechanisms that allow cells to colonise the brain are unclear. Methods: We have analysed matched and unpaired samples of breast cancer and brain metastases using morphology, immunophenotype and expression profiling and validated the data using in vitro cell culturing models and in vivo mice model. Results: Most of the brain metastases were triple negative and had a basal-like phenotype. Metastatic cells to the brain over-expressed HER3 compared to primaries and showed evidence of higher activation of the MAPK pathways. Inhibition using anti-neuregulin antibody, Herceptin and Lapatinib reduced tumour growth in vitro and in vivo. Conclusions: The data demonstrate activation of neuregulin-HER3 pathway in brain metastases from breast cancer and suggest that even in absence of HER2 amplification (as with triple negative and basal cancers), anti-epidermal growth factor receptor family inhibitors may have a role in treating these patients.
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Project description:Primary objectives: Phase Ib: To estimate the MTD(s) and/or RP2D(s) of the triple combination of WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant CRC harboring upstream Wnt pathway mutations.
Phase II: To estimate the preliminary anti-tumor activity of the RP2D(s) of WNT974 in combination with LGX818 and cetuximab in patients with BRAFV600-mutant CRC harboring upstream Wnt pathway mutations
Note:
Further enrollment to the study has been discontinued as of 21 March 2016. Therefore, references to phase II study design and objectives are no longer relevant.
Primary endpoints: 1. Phase Ib: To estimate the MTD(s)/RP2D(s) of the triple combination of WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant, KRAS wild-type (WT) mCRC harboring upstream Wnt pathway mutations, as measured by incidence of dose-limiting toxicities (DLTs) and exposure to WNT974 and LGX818 as measured by PK parameters.
2. Phase II: To estimate the preliminary anti-tumor activity at the RP2D(s) of the combination of WNT974, LGX818 and cetuximab, in patients with BRAFV600-mutant metastatic colorectal cancer harboring upstream Wnt pathway mutations, based on the Overall Response Rate (ORR).
Note: Further enrollment to the study has been discontinued as of 21 March 2016. Therefore, references to phase II study design and objectives are no longer relevant.
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