CAMP response element-binding protein mediates immune-evasion of KRAS-mutant lung adenocarcinomas
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ABSTRACT:
PROVIDER: PRJNA658142 | ENA |
REPOSITORIES: ENA
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Project description:We discovered that KRAS-mutant lung adenocarcinomas (LADC) co-opt CREB in order to evade the innate immune system: KRAS-driven CREB activation in LADC suppresses the expression of CXCR1 ligands that would otherwise recruit neutrophils to the tumor site. CREB was overexpressed in murine KRAS-mutant LADC, pulmonary Creb1-deletion inhibited disease development, and Creb1-overexpression boosted the tumorigenicity of KRAS-mutant cells. Conditional Creb1 deletion in Kras-mutant LADC cells caused overexpression of CXCR1/2 ligands, and lung tumor-bearing Creb1-deleted mice displayed increased pulmonary neutrophils. Cxcr1-deficient mice were selectively permissive to KRAS-mutant tumor growth and showed defective neutrophil recruitment. The pro-tumor effects of CREB required intact host-Cxcr1 and those of host-Cxcr1 necessitated mutant KRAS in cancer cells. Pharmacologic CREB blockade prevented tumor growth and restored neutrophil recruitment only when initiated before immune evasion of KRAS-mutant LADC cells. CREB and CXCR1 expression were respectively restricted to tumor and stromal cells of human LADC, while CREB-controlled genes profoundly impacted survival. In summary, CREB-mediated immune evasion of KRAS-mutant LADC rests on signaling to myeloid CXCR1 and is actionable.
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Project description:Immune evasion is a hallmark of KRAS-driven cancers, but underlying mechanism and clinical implications remain unclear.
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Project description:We used CRISPR/Cas9 genome editing to inactivate KRAS in pancreatic cancer cells and isolated cell populations that still produce tumors in mice. We show that the malignant phenotype of KRAS knockout cells is stable. However, KRAS deficient cancer cells fail to avoid detection and elimination by the host immune system, indicating that a key aspect of tumor maintenance by oncogenic KRAS is to promote immune evasion. Our study uncovers changes both in cancer cells and stromal immunoreactive cells attributable to KRAS expression. Complementation studies indicate that BRAF, AKT and MYC are causative drivers of KRAS-mediated immune suppression. These results show that combination treatments that both target KRAS signaling and boost antitumor immunity will be an effective strategy to treat PDAC.
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Project description:Glycosphingolipid synthesis mediates immune evasion in Kras-driven cancer
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Project description:Hormones and nutrients often induce genetic programs via signaling pathways that interface with gene-specific activators. Activation of the cAMP pathway, for example, stimulates cellular gene expression by means of the PKA-mediated phosphorylation of cAMP-response element binding protein (CREB) at Ser-133. Here, we use genome-wide approaches to characterize target genes that are regulated by CREB in different cellular contexts. CREB was found to occupy approximately 4,000 promoter sites in vivo, depending on the presence and methylation state of consensus cAMP response elements near the promoter. The profiles for CREB occupancy were very similar in different human tissues, and exposure to a cAMP agonist stimulated CREB phosphorylation over a majority of these sites. Only a small proportion of CREB target genes was induced by cAMP in any cell type, however, due in part to the preferential recruitment of the coactivator CREB-binding protein to those promoters. These results indicate that CREB phosphorylation alone is not a reliable predictor of target gene activation and that additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter.
2006-05-09 | E-WMIT-11 | biostudies-arrayexpress
Project description:In this dataset, we include expression data from 36 KRAS-mutant lung adenocarcinomas from Stage 1 of the BATTLE-2 trial, reflecting patients whose disease has relapsed or progresses following at least one front-line metastatic chemotherapy regimen. Tumor biopsy was performed following informed consent and prior to randomisation to one of the four possible treatment arms.
2015-10-01 | GSE61913 | GEO
Project description:RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We found that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential expression, are preferentially released in extracellular vesicles, and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas in vivo. Moreover, mutant KRAS induces the epigenetic reprogramming of IFN-stimulated genes (ISGs), some of which are also regulated by KZNFs. Our results reveal that mutant KRAS remodels the noncoding transcriptome via KZNF-mediated epigenomic reprogramming, revealing the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway.
2022-07-19 | GSE120566 | GEO
Project description:In this manuscript, we have used RNA-Sequencing experiment to obtain and integrate a variety of genomic features in order to identify signaling pathways that are associated to mutant KRAS lung tumors. 8 lung adenocarcinomas with mutant KRAS in lung tumors and 8 lung adenocarcarcinomas without KRAS mutation of which one sample is ran twice for QC purposes.
2012-06-07 | E-GEOD-34914 | biostudies-arrayexpress
Project description:KRAS drives immune evasion in a genetic model of pancreatic cancer
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Project description:Identification of genes up-regulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. To elucidate molecular characteristics of lung adenocarcinomas (ADCs) with ALK mutations and those without EGFR, KRAS and ALK mutations, 226 primary lung ADCs of pathological stage I-II, examined for the status of EGFR, KRAS and ALK mutations, were subjected to genome-wide expression profiling, and genes up-regulated in lung ADCs with ALK mutations and those without EGFR, KRAS and ALK mutations were identified. One hundred and seventy-four genes, including ALK, were selected as being up-regulated specifically in 79 lung ADCs without EGFR and KRAS mutations. These 79 cases were divided into: 11 cases of ALK-positive ADCs, 36 cases of group A triple-negative ADCs, and 32 cases of group B triple-negative ADCs, by unsupervised clustering according to the expression of the 174 genes. In ALK-positive ADCs, 30 genes, including ALK itself and GRIN2A, were significantly overexpressed. Group A triple-negative ADC cases showed significantly worse prognoses for relapse and death than ADC cases with EGFR, KRAS or ALK mutations and group B triple-negative ADC cases. Nine genes were identified as being significantly up-regulated in group A triple-negative ADC cases and critical for predicting their prognosis. The nine genes included DEPDC1, which had been identified as a candidate diagnostic and therapeutic target in bladder and breast cancers. Genes discriminating this group of ADCs will be useful for selection of patients who will benefit from adjuvant chemotherapy after surgical resection of stage I-II triple-negative ADCs and also informative for the development of molecular targeting therapies for these patients. Expression profiles in of 226 lung adenocarcinomas (127 with EGFR mutation, 20 with KRAS mutation, 11 with EML4-ALK fusion and 68 triple negative cases).
2011-11-01 | E-GEOD-31210 | biostudies-arrayexpress