KRAS drives lung cancer metastasis through lncRNA-mediated transcriptional and post-transcriptional regulation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA512868 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-12-17 | GSE124631 | GEO
Project description:Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer (CRC), KRAS* has been shown to suppress anti-tumor immunity which promotes tumor metastasis. Here, we show that the protumor actions of KRAS* extend to the adipogenic transformation of fibroblasts into lipid-laden cancer-associated fibroblasts (CAFs), which spur angiogenesis. Mechanistically, KRAS*-mediated activation of the transcription factor CP2 (TFCP2) resulted in TFCP2-mediated transcriptional upregulation of pro-adipogenic factors BMP4 and WNT5B to drive lipid-rich CAF transformation. Functionally, these lipid-rich CAFs promoted tumor growth via their production of vascular endothelial growth factor A (VEGFA). Correspondingly, genetic and pharmacological neutralization of TFCP2 decreased the abundance of lipid-rich CAFs, reduced tumor angiogenesis, and increased survival in an autochthonous KRAS*–driven CRC mouse model. These murine findings mirror translational profiles in human CRC. Thus, KRAS* transforms the stromal cell state to promote tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*–driven CRC.
2023-09-15 | GSE229559 | GEO
Project description:Ras family oncogenes are mutated in approximately 30% of human cancers and cause resistance to multiple treatment modalities. While identifying methods to directly target mutant KRas have been challenging, targeting regulators of KRas may be beneficial. Using a systems approach of integrating a genome-wide miRNA screen with patient data of a phospho-proteomic signature of the KRas downstream pathway, we identified miR-193a-3p as a potent tumor suppressor capable of reversing KRas-related signaling, whereby the 3’UTR of KRas is directly targeted via two miR-193a-3p binding sites. Mechanistic studies revealed that miR-193a-3p inhibited the KRas protein signature, KRas downstream transcriptomic network, proliferation, induced a G1 arrest, and reduced colony formation in 3D cultures through direct targeting of KRas. An ex vivo lung cancer model showed that miR-193a-3p significantly reduced the viability of circulating tumor cells as well as decreased metastasis. In vivo studies revealed that miR-193a-3p significantly reduced tumor growth as well as metastasis of a KRas-mutant lung cancer xenograft model.
2016-09-18 | GSE73194 | GEO
Project description:We performed a genome-wide analysis of lncRNA expression to identify novel targets for the further study of liver metastasis in CRC. Samples obtained from CRC patients were analyzed using Arraystar human 8Ã?60K lncRNA/mRNA v3.0 microarrays chips to find differentially expressed lncRNAs and mRNAs; The results were confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The differentially expressed lncRNAs and mRNAs were identified through fold-change filtering. Gene ontology (GO) and pathway analyses were performed using standard enrichment computational methods. Twelve primary CRC samples were obtained from six patients with CRC and liver metastasis (Exp G) and six patients with CRC without metastasis (Ctrl G).
2016-05-18 | E-GEOD-75050 | biostudies-arrayexpress
Project description:Long non-coding RNAs (lncRNA) have emerged as important regulators of gene expression at both the transcriptional and post-transcriptional levels. While altered expressions of lncRNAs have been observed in breast cancer (BCa) development, their roles in BCa progression and metastasis are still poorly understood. To identify novel BCa-associated lncRNA candidates, we have employed a high-density SNP array based approach to uncover lncRNA genes at intergenic region that are aberrantly expressed in BCa. Here we report the role of a novel lncRNA, LincIN, in breast cancer progression and metastasis. High levels of LincIN expression are frequently observed in tumors compared to adjacent normal tissues, and are strongly associated with aggressive breast cancers. Importantly, analysis of The Cancer Genome Atlas (TCGA) data further suggested that high LincIN expression was associated with poor overall survival in patients with breast cancer (P<0.05). Our gain-and-loss experiments demonstrate that LincIN play a role in tumor cell migration and invasion and knockdown of LincIN diminishes tumor cell invasion in vitro and lung metastasis in a mouse xenograft model. We also identified a LincIN-binding protein complex, NF90/NF45, through which LincIN destabilizes tumor suppressor p21 mRNA post-transcriptionally and thereby represses its protein expression. In summary, our findings delineated an oncogenic role of LincIN in breast tumor progression-metastasis, and mechanistically uncovered its cooperative actions with NF90/NF45 in regulating tumor suppressor gene expression at the post-transcriptional level.
2017-03-01 | GSE79214 | GEO
Project description:Genome-wide analyses have identified thousands of long non-coding RNAs (lncRNAs). Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) is among the most abundant lncRNAs whose expression is altered in numerous cancers. Here we report that genomic loss, as well as systemic knockdown of Malat1 using antisense oligonucleotides, in the MMTV-PyMT mouse mammary carcinoma model results in slower tumor growth accompanied by differentiation into highly cystic tumors and a significant reduction in lung metastasis. Further, Malat1 loss results in a reduction of branching morphogenesis in MMTV-PyMT and Her2/neu amplified tumor organoids consistent with the in vivo reduction in lung metastasis. At the molecular level, Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and pro-tumorigenic signaling pathways. Together, these data indicate that the lncRNA Malat1 regulates critical processes in mammary cancer pathogenesis and represents a promising therapeutic target for inhibiting breast cancer metastasis. Transcriptome profiles of tumors and organoids after Malat1 knockdown using antisense olgonucleotides (ASOs).
2016-01-12 | E-GEOD-67647 | biostudies-arrayexpress
Project description:The purpose of this study is to identify lncRNAs involved in the pathology of colorectal cancer (CRC) liver metastasis and investigate their underlying mechanisms. A total of 439 miRNAs were identified to be differentially expressed between 7 primary CRC tissues with liver metastases and 8 CRC tissues without liver metastases from 15 patients by Arraystar lncRNA microarrays
2017-02-28 | GSE95423 | GEO
Project description:Oncogenic KRAS signaling is required for tumor survival in cancers that harbor KRAS mutations. We recently performed a genome-scale expression screen to identify genes that bypass KRAS dependency. Here we demonstrate that the developmental transcription factor LHX9 rescues KRAS suppression in vitro and xenograft models. Furthermore, LHX9 decreases cell sensitivity to KRASG12C and MEK1/2 inhibitors. LHX9 promotes transcriptional changes associated with KRAS. Importantly, YAP1 upregulation by LHX9 is required for the rescue of KRAS suppression. Together we identify LHX9 as a YAP1 transcriptional regulator that permits KRAS-dependent cells to proliferate without KRAS expression.
2018-12-01 | GSE116823 | GEO
Project description:Oncogenic KRAS signaling is required for tumor survival in cancers that harbor KRAS mutations. We recently performed a genome-scale expression screen to identify genes that bypass KRAS dependency. Here we demonstrate that the developmental transcription factor LHX9 rescues KRAS suppression in vitro and xenograft models. Furthermore, LHX9 decreases cell sensitivity to KRASG12C and MEK1/2 inhibitors. LHX9 promotes transcriptional changes associated with KRAS. Importantly, YAP1 upregulation by LHX9 is required for the rescue of KRAS suppression. Together we identify LHX9 as a YAP1 transcriptional regulator that permits KRAS-dependent cells to proliferate without KRAS expression.
2018-12-01 | GSE116822 | GEO
Project description:Primary pneumocytes from KRas;Atg5fl/+ and KRas;Atg5fl/fl littermates were cultured for 48 hours and infected with AdCre-GFP to induce expression of the KrasG12D oncogene and concomitant Atg5 deletion. The transcriptional profile of those cells was determined by mRNA sequencing and uncovered differential expression in cellular movement, inflammatory response and oxidative stress response. Comparison of transcriptomes from KRas;Atg5fl/+ and KRas;Atg5fl/fl pneumocytes
2014-01-07 | E-GEOD-48387 | biostudies-arrayexpress