Inhibition of ADAM9 mediates KRAS-related pathways in pancreatic cancer cells
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ABSTRACT:
PROVIDER: PRJNA1030022 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26443891_1.fastq.gz | Fastqsanger.gz | |||
| SRR26443891_2.fastq.gz | Fastqsanger.gz | |||
| SRR26443892_1.fastq.gz | Fastqsanger.gz | |||
| SRR26443892_2.fastq.gz | Fastqsanger.gz |
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Project description:ADAM9 deficiency mediates KRAS related pathways in pancreatic cancer cells
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Project description:Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here we identify a disintegrin and metalloproteinase domain 9 (ADAM9) as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor-1 (PAI-1), which functions as a selective autophagy receptor in conjunction with LC3, triggering the lysosomal degradation of KRAS. Suppression of ADAM9 by a small molecule inhibitor restricts disease progression in spontaneous models, and the combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.
2023-12-11 | GSE245560 | GEO
Project description:Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here we identify a disintegrin and metalloproteinase domain 9 (ADAM9) as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor-1 (PAI-1), which functions as a selective autophagy receptor in conjunction with LC3, triggering the lysosomal degradation of KRAS. Suppression of ADAM9 by a small molecule inhibitor restricts disease progression in spontaneous models, and the combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.
2023-12-11 | GSE245819 | GEO
Project description:We utilized non-transformed, human pancreatic ductal epithelial (HPDE) cells, previously engineered with the E6 and E7 proteins of the HPV16 virus to emulate loss of p53 and inactivation of the Rb pathway, respectively. Given the frequent activation of KRAS (>90% PDAC tumors) and its early role in pancreatic neoplasia, we sought to engineer HPDE cells containing KRASG12D to provide the appropriate context in which to screen for novel drivers that might represent KRAS effectors. The KRAS-induced transcription analysis was conducted using RNAs extracted from HPDE cells transduced with either control, wild-type KRAS or KRASG12D(pInducer) with or without DOX (100ng/ml) for 72 h, followed by hybridization of labeled cDNA onto Agilent arrays (Agilent G3 Human GE 8x60K) by the Baylor College of Medicine Genome Profiling Core Facility. multi-group comparison
2016-01-19 | E-GEOD-58055 | biostudies-arrayexpress
Project description:That mutational activation of Kras and inactivation of p16 are two signature genetic alterations required for development of PDAC. To elucidate the downstream pathways activated by oncogenic Kras and inactivated p16 in human pancreatic tumorigenesis, we profiled gene expression in HPNE/Kras/shp16 and HPNE/Kras cells using cDNA microarray analysis.
2016-11-03 | GSE89422 | GEO
Project description:Pancreatic cancer is characterised by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered Kras gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic KRAS mutation is well characterised, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrate that wild-type Kras restrains the oncogenic impact of mutant Kras, and drastically impacts both Kras-mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increases oncogenic Kras signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated Myc levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type Kras sensitises Kras mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type Kras during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.
2024-09-22 | GSE277392 | GEO
Project description:We utilized the inducible and reversible iKras* genetically engineered mouse model to intiate oncogenic Kras (Kras*) expression in the pancreatic epithelium by providing mice with doxycycline water, and then switched mice to regular water thereby turning expression of Kras* off for 3 days, 3 weeks post-induction of acute pancreatitis. Single cell RNA sequencing revealed that fibroblasts are reprogrammed by signals originating from epithelial Kras*-expressing cells to shape the immune microenvironment during pancreatic tumorigenesis.
2022-02-14 | GSE179846 | GEO
Project description:We have carried out transcriptional profile analysis in WT MICE and bitransgenic Pdx1-cre/Kras*A MICE baring Pancreatic Ductal Adenocarcinoma Mouse models faithfully simulating human cancer are valuable for genetic identification of potential drug-targets but, among them, the most advantageous for practical use in subsequent preclinical testing of candidate therapeutic regimes are those exhibiting rapid tumor development. Considering that a KRAS mutation (predominantly in codon 12, such as KRASG12D; KRAS*) occurs with high frequency (~90%) in cases of human pancreatic ductal adenocarcinoma (PDA)1, we sought to develop a mouse PDA model that would exhibit high tumor incidence and short latency by ectopic overexpression of Kras*. Five WT mice and 6 bitransgenic Pdx1-cre/Kras*A MICE baring Pancreatic Ductal Adenocarcinoma were used to identify key genes in the formation of panceatic malignacies
2014-09-01 | E-GEOD-53659 | biostudies-arrayexpress
Project description:GATA6 is a master regulator of differentiation in the pancreas and its expression levels determine the two main molecular subtypes of pancreatic cancer. High GATA6 contributes to the “classical” pancreatic cancer subtype, which is associated with a higher degree of tumor differentiation and better disease prognosis. However, why GATA6 expression varies across pancreatic cancers and what regulate GATA6 expression remain elusive. Here we report that the oncogenic KRAS-activated ERK signaling suppresses GATA6 transcription in pancreatic cancers. GATA6 mRNA levels inversely correlated with KRAS/ERK activity in pancreatic tumors. A genome-wide CRISPR screen in a GATA6-EGFP reporter knockin cell line identified JUNB as the ERK-regulated transcriptional repressor for GATA6. Active ERK stabilizes JUNB protein while KRAS/ERK inhibition led to ubiquitin-independent proteasomal degradation of JUNB and increased transcription of GATA6. Up-regulation of GATA6 enhanced chemosensitivity of pancreatic cancer cells and KRAS/ERK inhibitors synergized with chemotherapy in a GATA6-dependent manner. Our study identifies how oncogenic KRAS/ERK signaling suppresses GATA6 to cause dedifferentiation in pancreatic cancer. Combining KRAS/ERK inhibitors with standard-of-care chemotherapies could be a promising therapeutic strategy for treating pancreatic cancers.
2025-11-20 | GSE307506 | GEO
Project description:Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways GSK-3 inhibition at 2 and 8 hours
2013-05-31 | E-GEOD-42559 | biostudies-arrayexpress