MYC causes Suppression of Anti-Tumor Immune Response
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA888073 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21837854.fastq.gz | Fastqsanger.gz | |||
| SRR21837855.fastq.gz | Fastqsanger.gz | |||
| SRR21837856.fastq.gz | Fastqsanger.gz | |||
| SRR21837857.fastq.gz | Fastqsanger.gz | |||
| SRR21837858.fastq.gz | Fastqsanger.gz |
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Project description:The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Em-tTA/tetO-MYC T-acute lymphomablastic lymphoma (T-ALL), some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express high levels of either transgenic or endogenous Myc suggesting that tumors continue to be addicted to oncogenic levels of MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator (tTA) resulting in expression of the MYC transgene even in the presence of doxycycline. Many of the remaining recurring tumors expressed high levels of endogenous Myc which was in some cases associated with a genomic rearrangement of the endogenous Myc locus or overexpression of Notch1. Gene expression profiling confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis confirming that these tumors remain oncogene addicted. These results suggest that tumors caused by MYC overexpression remain addicted to high levels of expression of this oncogene. 13 samples, no replicates included
2011-09-23 | E-GEOD-32341 | biostudies-arrayexpress
Project description:The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Em-tTA/tetO-MYC T-acute lymphomablastic lymphoma (T-ALL), some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express high levels of either transgenic or endogenous Myc suggesting that tumors continue to be addicted to oncogenic levels of MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator (tTA) resulting in expression of the MYC transgene even in the presence of doxycycline. Many of the remaining recurring tumors expressed high levels of endogenous Myc which was in some cases associated with a genomic rearrangement of the endogenous Myc locus or overexpression of Notch1. Gene expression profiling confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis confirming that these tumors remain oncogene addicted. These results suggest that tumors caused by MYC overexpression remain addicted to high levels of expression of this oncogene.
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Project description:We recently established the ERK-dependent transcriptome and phosphoproteome in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). Of 1,718 ERK-dependent genes, 143 encode transcription factors. Of 2,123 ERK-dependent phosphoproteins, 98 are transcription factors. Despite this complexity, we observed that genetic suppression of the MYC transcription factor alone phenocopied KRAS suppression in signaling, growth and metabolic processes. To establish a molecular basis for MYC support of KRAS-ERK-driven PDAC growth, we determined the gene transcription changes caused by acute loss of MYC function and identified 1,685 MYC-dependent (UP) and 1,325 MYC-inhibited (DN) genes. Dependency Map analyses demonstrated that MYC UP but not DN genes are essential for PDAC growth. Instead, pathway analyses support MYC DN genes as a secondary RHO GTPase-mediated compensatory response to oncogenic stress. We found that 36% of ERK-dependent genes are MYC-dependent, supporting the dominant role of MYC in driving ERK-regulated gene expression. Finally, proteomic profiling revealed that MYC regulated a complex kinome comprised of protein kinases that likely contribute to MYC-driven cancer growth. We conclude that MYC supports KRAS-ERK-dependent PDAC growth through regulation of a complex transcriptome and kinome.
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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.
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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:Tumour suppression by immune system through stochastic oscillations
GiulioCaravagnaa
Albertod’Onofriob
PaoloMilazzoa
RobertoBarbutia
https://doi.org/10.1016/j.jtbi.2010.05.013
Abstract
The well-known Kirschner–Panetta model for tumour–immune System interplay [Kirschner, D., Panetta, J.C., 1998. Modelling immunotherapy of the tumour–immune interaction. J. Math. Biol. 37 (3), 235–252] reproduces a number of features of this essential interaction, but it excludes the possibility of tumour suppression by the immune system in the absence of therapy. Here we present a hybrid–stochastic version of that model. In this new framework, we show that in reality the model is also able to reproduce the suppression, through stochastic extinction after the first spike of an oscillation.
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