Fat promotes growth and invasion in a 3D microfluidic tumor model of triple-negative breast cancer
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ABSTRACT:
PROVIDER: PRJNA1293183 | ENA |
REPOSITORIES: ENA
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Project description:Diet influences the levels of small molecules that circulate in plasma and interstitial fluid, altering the biochemical composition of the tumor microenvironment (TME). These circulating nutrients have been associated with how tumors grow and respond to treatment, but it remains difficult to parse their direct effects on cancer cells. Here, we combine a three-dimensional (3D) microfluidic tumor model with physiologically relevant culture media to investigate how concentrations of circulating nutrients influence tumor growth, cancer cell invasion, and overall tumor metabolism. Human triple-negative breast cancer cells cultured in 2D under media conditions mimicking five different dietary states show no observable differences in proliferation or morphology. Nonetheless, those exposed to high-fat conditions exhibit increased metabolic activity and upregulate genes associated with motility and extracellular matrix remodeling. In the 3D microfluidic model, high-fat conditions accelerate tumor growth and invasion and induce the formation of hollow cavities. Surprisingly, the presence of these cavities does not correlate with an increase in apoptosis or ferroptosis. Instead, RNA-sequencing analysis revealed that high-fat conditions induce the expression of MMP1, consistent with cavitation via cell invasion. Mimicking the flow of circulating nutrients within the TME can thus be used to identify novel connections between metabolic states and tumor phenotype.
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Project description:ADAR1 catalyzes Adenosine-to-Inosine (A-to-I) editing of double-stranded RNA and regulates global expression output through its interactions with RNA and other proteins. ADARs play important roles in development and disease, and previous work has shown that ADAR1 is oncogenic in a growing list of cancer types. Here we show that ADAR1 is important for growth and invasion in triple negative breast cancer cells, as ADAR1 loss yields reduced growth, migration & invasion, and mammosphere formation. Global RNA-seq analyses demonstrate that ADAR1 regulates both coding and non-coding targets via expression level and/or A-to-I editing. We demonstrated that a recoding edit in FLNB (chr3:58156064) inhibits the tumor suppressive activities of the protein to promote growth & invasion. We show that several tumor suppressor microRNAs are also downregulated by ADAR1 to promote cell cycle progression and invasion. This work describes several novel mechanisms of ADAR1-mediated oncogenesis in triple negative breast cancer, providing support to strategies for targeting ADAR1 in this aggressive cancer type with few treatment options.
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Project description:ADAR1 regulates growth & invasion in triple-negative breast cancer
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Project description:Development of a reliable method for human triple-negative breast cancer organotypic culture: Improving imaging and genomic studies in 3D cultures The primary objectives of this study are to develop an advanced three-dimensional cell culture system to better model the tumor microenvironment in triple-negative breast cancer (TNBC), analyze the differences in molecular and cellular behavior between two-dimensional (2D) and 3D cultures, and investigate the impact of these differences on key oncogenic signaling pathways, specifically PI3K and β-catenin.
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Project description:Inter-patient and intra-tumoral heterogeneity complicate the identification of predictive biomarkers and effective treatments for basal triple negative breast cancer (b-TNBC). Invasion is the initiating event in metastasis and can occur by both collective and single-cell mechanisms. We cultured primary organoids from a b-TNBC genetically engineered mouse model in 3D collagen gels to characterize their invasive behavior. We observed that organoids from the same tumor presented different phenotypes that we classified as non-invasive, collective and disseminative. To identify molecular regulators driving these invasive phenotypes, we developed a workflow to isolate individual organoids from the collagen gels based on invasive morphology and perform RNA sequencing. We next tested the requirement of differentially regulated genes for invasion using shRNA knock-down. Strikingly, KRAS was required for both collective and disseminative phenotypes. We then performed a drug screen targeting signaling nodes upstream and downstream of KRAS. We found that inhibition of EGFR, MAPK/ERK, or PI3K/AKT signaling reduced invasion. Of these, ERK inhibition was striking for its ability to potently inhibit collective invasion and dissemination. We conclude that different cancer cells in the same b-TNBC tumor can express different metastatic molecular programs and identified KRAS and ERK as essential regulators of collective and single cell dissemination.
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Project description:Triple-negative breast cancer (TNBC) is defined by the absence of estrogen and progesterone receptors and human epidermal growth factor receptor 2, and is the most lethal and aggressive subtype of breast cancer. However, the genes which relate to promote tumor aggressiveness in TNBC remain unclear. In order to investigate specific genes and pathways involved in TNBC tumorigenesis, we compared genes differentially expressed between 3D cultures (3DC) or tumor xenograft models and control two-dimensional cultures (2DC). Total RNA was prepared from the TNBC cells under the condition of 2DC, 3DC and tumor xenograft models, and applied to Affymetrix Human Genome U133 Plus 2.0 Array.
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Project description:Triple-negative breast cancer (TNBC) is malignant cancer with a high risk of recurrence. To date, the underlying 3D chromatin organizations of TNBC have remained unclear. Here, using in situ Hi-C, we characterized the 3D chromatin organizations in cells representing five distinct subtypes of breast cancer (including TNBC) and TNBC tissues, compared to normal cells/tissues. We found that the global and local 3D architectures are severely disrupted in TNBC cells. Importantly, we detected CTCF-dependent TNBC-susceptible loss/gain of 3D chromatin organizations and found that these changes were strongly associated with perturbed chromatin accessibility and transcriptional dysregulations. Although some discrepancies exist between TNBC cell lines and tissues, we observed that perturbed local 3D architectures found in TNBC cells are partially conserved in TNBC tissues. Furthermore, we discovered distinct tissue-specific chromatin loops by comparing normal and TNBC tissues. Collectively, our findings provide important features of 3D chromatin organization in TNBC.
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Project description:Triple-negative breast cancer (TNBC) is malignant cancer with a high risk of recurrence. To date, the underlying 3D chromatin organizations of TNBC have remained unclear. Here, using in situ Hi-C, we characterized the 3D chromatin organizations in cells representing five distinct subtypes of breast cancer (including TNBC) and TNBC tissues, compared to normal cells/tissues. We found that the global and local 3D architectures are severely disrupted in TNBC cells. Importantly, we detected CTCF-dependent TNBC-susceptible loss/gain of 3D chromatin organizations and found that these changes were strongly associated with perturbed chromatin accessibility and transcriptional dysregulations. Although some discrepancies exist between TNBC cell lines and tissues, we observed that perturbed local 3D architectures found in TNBC cells are partially conserved in TNBC tissues. Furthermore, we discovered distinct tissue-specific chromatin loops by comparing normal and TNBC tissues. Collectively, our findings provide important features of 3D chromatin organization in TNBC.
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Project description:Triple-negative breast cancer (TNBC) is malignant cancer with a high risk of recurrence. To date, the underlying 3D chromatin organizations of TNBC have remained unclear. Here, using in situ Hi-C, we characterized the 3D chromatin organizations in cells representing five distinct subtypes of breast cancer (including TNBC) and TNBC tissues, compared to normal cells/tissues. We found that the global and local 3D architectures are severely disrupted in TNBC cells. Importantly, we detected CTCF-dependent TNBC-susceptible loss/gain of 3D chromatin organizations and found that these changes were strongly associated with perturbed chromatin accessibility and transcriptional dysregulations. Although some discrepancies exist between TNBC cell lines and tissues, we observed that perturbed local 3D architectures found in TNBC cells are partially conserved in TNBC tissues. Furthermore, we discovered distinct tissue-specific chromatin loops by comparing normal and TNBC tissues. Collectively, our findings provide important features of 3D chromatin organization in TNBC.
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