MYC-mediated immune supression in TNBC
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB43214 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The MYC oncogene is frequently amplified in triple negative breast cancer (TNBC). Here, we show that MYC suppression induces immune-related hallmark gene set signatures and tumor infiltrating T cells in MYC-hyperactivated TNBCs. Mechanistically, MYC repressed stimulator of interferon genes (STING) expression via direct binding to the STING enhancer region, resulting in downregulation of the T cell chemokines CCL5, CXCL10 and CXCL11. In primary and metastatic TNBC cohorts, tumors with high MYC expression or activity exhibited low STING expression. Using a CRISPR-mediated enhancer perturbation approach, we demonstrated that MYC-driven immune evasion is mediated by STING repression. STING repression induced resistance to PD-L1 blockade in mouse models of TNBC. Finally, a small molecule inhibitor of MYC combined with PD-L1 blockade elicited a durable response in immune-cold TNBC with high MYC levels, suggesting a strategy to restore PD-L1 inhibitor sensitivity in MYC-overexpressing TNBC.
2022-03-01 | GSE196324 | GEO
Project description:The MYC oncogene is frequently amplified in triple negative breast cancer (TNBC). Here, we show that MYC suppression induces immune-related hallmark gene set signatures and tumor infiltrating T cells in MYC-hyperactivated TNBCs. Mechanistically, MYC repressed stimulator of interferon genes (STING) expression via direct binding to the STING enhancer region, resulting in downregulation of the T cell chemokines CCL5, CXCL10 and CXCL11. In primary and metastatic TNBC cohorts, tumors with high MYC expression or activity exhibited low STING expression. Using a CRISPR-mediated enhancer perturbation approach, we demonstrated that MYC-driven immune evasion is mediated by STING repression. STING repression induced resistance to PD-L1 blockade in mouse models of TNBC. Finally, a small molecule inhibitor of MYC combined with PD-L1 blockade elicited a durable response in immune-cold TNBC with high MYC levels, suggesting a strategy to restore PD-L1 inhibitor sensitivity in MYC-overexpressing TNBC.
2022-03-01 | GSE196323 | GEO
Project description:Triple-negative breast cancer (TNBC) is the breast cancer (BC) subtype with the poorest outcome. The PIM family of kinases has recently emerged as a factor that is both overexpressed in TNBC samples and associated with poor outcomes. Preclinical data suggest that TNBC that exhibits an elevated MYC oncoprotein expression (MYC+TNBC), accounting for 50% of TNBC cases, is sensitive to PIM inhibition. However, ongoing clinical observations indicate that the efficacy of PIM inhibitors as single agents may be limited in solid tumors, suggesting the need for combination therapies. We conducted drug combination screens to identify a combination that targets PIM and the 20S proteasome (the PIMi/20Si combination) as the most synergistic combination. Following the screening, we used a chemical genetic approach to reveal that the mechanisms of drug synergy involve disruption of protein homeostasis and obstruction of an adaptive resistance mechanism associated with proteasome inhibition. Thus, the PIMi/20Si combination could represent a rational combination therapy against MYC+ TNBC that is readily translatable to early-stage clinical investigations.
2021-05-26 | MSV000087521 | MassIVE
Project description:Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC's poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor Sp1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.
2022-11-10 | GSE217474 | GEO
Project description:The expression levels of JMJD6 and its correlation with H2A.XY39ph differed in TNBC and non-TNBC cells. In addition, we have previously shown that H2A.XY39ph levels are positively correlated with tumor size, histological grade and advanced TNM stage in breast cancer. To analyze the role of JMJD6 in regulating the characteristics of different subtypes of breast cancer, the transcriptomes of TNBC cells (SUM159) and non-TNBC cells (HCC1569) that overexpressed JMJD6 were compared. We speculate that JMJD6 overexpression cause autophagy pathway activation in TNBC via enhancing ATG genes expression.
2023-10-01 | E-MTAB-6517 | biostudies-arrayexpress
Project description:Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer. Despite decades of intense investigation, treatment options remain limited and rapid recurrence with distant metastases remains a significant challenge in the clinic. Cancer cell-intrinsic production of cytokines such as type I interferons (IFN-I) is a known potent modulator of response to therapy in many cancers, including TNBC, and can influence therapeutic outcome. Here, we report that in TNBC systems the aryl hydrocarbon receptor (AhR) suppresses IFN-I expression via inhibition of Stimulator of Interferon Genes (STING), a key mediator of interferon production. Intratumoral STING activity is essential in mediating the efficacy of PARP inhibitors (PARPi) which are used in the treatment of cancers harboring BRCA-1 deficiency. We find that, in TNBC cells, PARPi treatment activates AhR in a BRCA1 deficiency-dependent manner, thus suggesting the presence of a negative feedback loop aimed at modulating PARPi efficacy. Importantly, our results indicate the combined inhibition of PARP and AhR is superior in elevating IFN-I expression as compared to PARPi-alone. Thus, AhR inhibition may allow for enhanced IFN-I production upon PARPi in BRCA1-deficient breast cancers, most of which are of TNBC origin, and may represent a therapeutically viable strategy to enhance PARPi efficacy.
2024-01-31 | GSE252119 | GEO
Project description:We profiled gene expression and splicing changes in HCC1806 human TNBC cells overexpressing three splicing factor genes (SRSF2-SRSF3-SRSF7), all three splicing factors (called 3xSR) or MYC. We performed RNA-seq, in triplicate on 3xSR, MYC-OE, triple plasmid control, SRFS2, SRSF3, SRSF7, or single plasmid control HCC1806 cells.
2022-07-11 | GSE181956 | GEO
Project description:Inhibition of TNBC metastasis by Gpx1
| PRJNA522914 | ENA
Project description:The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to an imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depleted key TCA cycle metabolites and, in combination with MYC activation, led to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses revealed that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC- driven lymphoma in vivo. In summary, glutamine supports the viability of MYC- overexpressing cells through an energetic rather than a biosynthetic mechanism.
2022-08-11 | PXD034517 | Pride
Project description:Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKC lambda) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKC lambda impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKC lambda phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKC lambda controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a new therapeutic strategy for treatment of malignant cancers, like angiosarcoma.
2019-11-12 | PXD011595 | Pride