Apolipoprotein E promotes immune suppression in pancreatic cancer through NF-kB-mediated production of CXCL1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA673706 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12960951_1.fastq.gz | Fastqsanger.gz | |||
| SRR12960951_2.fastq.gz | Fastqsanger.gz | |||
| SRR12960952_1.fastq.gz | Fastqsanger.gz | |||
| SRR12960952_2.fastq.gz | Fastqsanger.gz | |||
| SRR12960953_1.fastq.gz | Fastqsanger.gz |
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Project description:This study sought to determine the role of Apolipoprotein E (ApoE) in mediating immune suppresion in pancreatic cancer. Our data show ApoE regulates T cell infiltration through NF-kB mediated Cxcl1 production.
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Project description:NF-kB has been linked to doxorubicin-based chemotherapy resistance in breast cancer patients. NF-kB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined, however its functional consequences in terms the spectrum of NF-kB -dependent genes expressed and, thus, the impact on tumour cell behaviour are unclear. We hypothesized that NF-kB gene expression profile induced by doxorubicin might be different among breast cancer cells and tumors. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-kB driven-gene transcription demonstrated by gene expression microarrays. Selected genes (ICAM-1, CXCL1, IL8) related with invasion, metastasis and chemoresistance expression were confirmed by RT-PCR in a subset of additional doxorubicin-treated cells and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of these NF-kB targeted genes. Overexpression of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-kB driven transcription induced by doxorubicin. Moreover, tumors with a p53 deficient background and nuclear NF-kB /p65 expression correlated with reduced disease free-survival. This study supports that tumor molecular profiles for doxorubicin driven NF-kB-response are likely to exist. A link between p53 deficiency and the presence of active transcriptionally NF-kB could favour an aggressive behaviour and might have implications for doxorubicin-based chemotherapy in breast tumors exhibiting aberrant p53 activity 12 samples were analyzed: controls (n=3); Doxorubicin treated (n=3); MLN120B treated (n=3); MLN120B + Doxorubicin treated (n=3)
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations alter cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we demonstrate that p53R172H enhances tumor growth, establishes a suppressive TME by inducing immune evasion, and blunts the effectiveness of immune checkpoint inhibitors (ICIs). We discovered that the oncogenic function of p53R172H is mediated by upregulation of the immunosuppressive chemokine Cxcl1. Mechanistically, we show that p53R172H binds to the distal enhancers of the Cxcl1 gene and increases enhancer activity and Cxcl1 expression. NF-kB also occupies Cxcl1 enhancers, and p53R172H binds these enhancers in an NF-kB-dependent manner, suggesting a role of NF-kB in commuting p53R172H to the Cxcl1 enhancers. Our findings elucidate how a common mutation in a critical tumor-suppressor gene exploits enhancers to modulate chemokine gene expression and foster an immunosuppressive TME in PDAC that undermines the efficacy of ICI.
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