Next Generation Sequencing Quantitative Analysis of altered expression of genes in KRASG12D PDAC tissues
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE234927 | GEO | 2023/09/20
REPOSITORIES: GEO
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Project description:Almost all human pancreatic ductal adenocarcinomas (PDACs) are driven by oncogenic Kras and the progression of the disease is characterized by the serial appearance of certain genetic lesions. Mouse models have convincingly shown that Kras mutation induces classical PanIN lesions that can progress to PDAC in the appropriate tumor suppressor background. However, the cooperative mechanism between mutant Kras-dependent signaling surrogates and other oncogenic pathways remains to be fully elucidated in order to devise better therapeutic strategy. Mounting evidence PTEN/PI3K perturbation on PDAC tumorigenesis, we observed frequent PTEN inactivation at both genomic and histopathological levels in primary human PDAC samples. The importance of PTEN/PI3K pathway during the development of PDAC was further supported by genetic studies demonstrating that Pten deficiency in cooperation with Kras activation accelerated the formation of invasive PDAC. Mechanistically, combined Kras mutation and Pten inactivation leads to NFkB activation and subsequent induction of cytokine pathways, accompanied with strong stromal activation and immune cell infiltration. Therefore, PTEN/PI3K pathway dictates the activity of NFkB network and serves as a major surrogate during Kras-mediated pancreatic tumorigenesis. Primary pancreatic ductal epithelial cell cultures were established from 6 week old Pdx1-Cre;LSL-KrasG12D L/+ (n=3) or Pdx1-Cre;LSL-KrasG12D L/+;Pten L/+ (n=5) mice. Total RNA was collected from early passage cells.
2011-08-31 | E-GEOD-25828 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 anti-tumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.
2023-06-09 | GSE234449 | GEO
Project description:The maintenance of advanced malignancies relies on continued activity of driver oncogenes, although their rate-limiting role is highly context-dependent with respect to tumor types and associated genetic alterations. Oncogenic Kras mutation is the signature event in human pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven p53 mutant PDAC mouse model establishes that advanced PDAC remains strictly dependent on continued KrasG12D expression and that KrasG12D serves a vital role in the control of tumor metabolism, through stimulation of glucose uptake and channeling of glucose intermediates through the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Notably, these studies reveal that oncogenic Kras regulates ribose biogenesis. Unlike canonical models of PPP-mediated ribose biogenesis, we demonstrate that oncogenic Kras drives intermediates from enhanced glycolytic flux into the non-oxidative arm of the PPP, thereby decoupling ribose biogenesis from NADPNADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in Kras-driven PDAC. Primary pancreatic tumor lines were established from p48Cre tetO_LKrasG12D ROSA_rtTAL+ p53L+ mice. Five independent tumor lines (iKras1-5) were used for pancreatic injection into nude mice to generate orthotopic tumors. The mice were kept on doxycycline for 2 weeks until obvious tumor formation. Half of the animals were pulled off doxycycline for 24 hours. Tumors with over 75% cellularity were collected for total RNA prepartion. For in vitro expression profiles, the same five tumor lines were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared. For control samples, two independent tumor lines from LSL-KrasG12D p53L+ tumors were cultured in the presence or absence of doxycycline for 24 hours and total cellular RNA was prepared.
2012-04-29 | E-GEOD-32277 | biostudies-arrayexpress
Project description:Constitutive Kras and NF-kappaB activation is identified as signature alterations in human pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms of constitutive NF-kappaB activation in KrasG12D-induced PDAC are not yet understood. Here, we report that pancreas-targeted IKK2/beta inactivation inhibited NF-kappaB activation and completely suppressed PDAC development in KrasG12D and KrasG12D;Ink4a/Arf mutant mice, demonstrating a genetic link between IKK2/beta and KrasG12D in PDAC inception. Our findings reveal that KrasG12D-activated AP-1 induces IL-1alpha, which in turn activates NF-kappaB and its target genes IL-1alpha and p62, to initiate IL-1alpha/p62 feedforward loops for inducing and sustaining NF-kappaB activity. Furthermore, IL-1alpha overexpression correlates with Kras mutation, constitutive NF-kappaB activity, and poor survival in PDAC patients. Therefore, our findings establish a pathway linking duel feedforward loops of IL-1alpha/p62 through which IKK2/beta/NF-kappaB is activated by KrasG12D. To study Kras-induced inflammatory responses and to identify differentially expressed genes between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice, cDNA microarray analysis was performed.
2012-01-24 | E-GEOD-27478 | biostudies-arrayexpress
Project description:We analyzed chromatin accessibility genome wide in EZH2KO and control cells derived from PDAC tumors of KrasG12D/PEC-IkkαΔPEC PDAC model mice to gain insight how the ablation of EZH2 affects the accessibility of genes involved in PDAC tumorigenesis.
2021-12-31 | GSE148335 | GEO
Project description:Rhabdomyosarcoma is a pediatric malignancy thought to arise from the uncontrolled proliferation of myogenic cells. Here, we have generated models of rhabdomyosarcoma in the zebrafish by inducing oncogenic KRASG12D expression at different stages during muscle development. Several zebrafish promoters were used including the cdh15 and rag2 promoters that drive gene expression in early muscle progenitors, and the mylz2 promoter that expresses in differentiating myoblasts. The tumors that developed differed in their ability to recapitulate normal myogenesis. cdh15:KRASG12D and rag2:KRASG12D fish developed tumors that displayed an inability to fully undergo muscle differentiation by histologic appearance and gene expression analyses. In contrast, mylz2:KRASG12D tumors more closely resembled mature skeletal muscle and were most similar to well-differentiated human rhabdomyosarcoma by gene expression. mylz2:KRASG12D fish showed significantly improved survival compared to cdh15:KRASG12D and rag2:KRASG12D fish. Tumor-propagating activity was enriched in myf5-expressing cell populations within all of the tumor types. Our results demonstrate that oncogene expression at different stages during muscle development has profound effects on the ability of tumor cells to recapitulate normal myogenesis, altering the tumorigenic capability of these cells. 32 samples total: 7 WT muscle, 9 mylz2-KRAS, 9 cdh15-KRAS, and 7 rag2-KRAS tumors
2013-07-17 | E-GEOD-39731 | biostudies-arrayexpress
Project description:Pancreatic adenocarcinoma (PDAC) is a lethal disease and it is the most common type of pancreatic cancer. Majority of the pancreatic cancers harbor alterations in the Kras gene. Currently there are no approved drugs that target Kras directly and it's downstream effect on the epigenome remains unknown. In this study, we investigated the epigenetic landscape of pancreatic cancer cells which harbor the inducible KrasG12D allele. We performed RNA-seq, ChIP-seq against 6 different histone marks, ATAC-seq and RRBS to assess the changes in the epigenome after oncogenic KrasG12D induction.
2021-09-06 | E-MTAB-10900 | biostudies-arrayexpress
Project description:Activating mutations of the KRAS gene are found in >90% of pancreatic ductal adenocarcinoma (PDAC) cases. However, direct pharmacological targeting of the activated KRAS protein has been challenging. We previously reported that KR12, a DNA-alkylating pyrrole-imidazole polyamide designed to recognize the KRAS G12D/V mutation, showed an anti-tumor effect in colorectal cancer. In this study, we evaluated the anti-tumor effect of KR12 in PDAC. We found that KR12 inhibited tumor growth in a spontaneous PDAC mouse model, although the anti-tumor activity appeared to be limited in a human PDAC xenograft model. We developed a pyrrole-imidazole polyamide screening process based on the hypothesis that genetic elements otherwise unaffected by KR12 could exert attenuating effects on KRAS-suppression-resistant PDAC. We identified RAD51 as a potential therapeutic target in human PDAC cells. A RAD51 inhibitor showed an inhibitory effect on cell growth and affected the cytotoxic activity of KR12 in PDAC cells. These data suggested that the simultaneous inhibition of RAD51 and mutant KRAS blockage would be an important therapeutic strategy for PDAC.
2023-04-25 | GSE208243 | GEO
Project description:The maintenance of advanced malignancies relies on continued activity of driver oncogenes, although their rate-limiting role is highly context-dependent with respect to tumor types and associated genetic alterations. Oncogenic Kras mutation is the signature event in human pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven p53 mutant PDAC mouse model establishes that advanced PDAC remains strictly dependent on continued KrasG12D expression and that KrasG12D serves a vital role in the control of tumor metabolism, through stimulation of glucose uptake and channeling of glucose intermediates through the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Notably, these studies reveal that oncogenic Kras regulates ribose biogenesis. Unlike canonical models of PPP-mediated ribose biogenesis, we demonstrate that oncogenic Kras drives intermediates from enhanced glycolytic flux into the non-oxidative arm of the PPP, thereby decoupling ribose biogenesis from NADPNADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in Kras-driven PDAC.
2012-04-30 | GSE32277 | GEO
Project description:Pancreatic adenocarcinoma (PDAC) is a lethal disease and it is the most common type of pancreatic cancer. Majority of the pancreatic cancers harbor alterations in the Kras gene. Currently there are no approved drugs that target Kras directly and it's downstream effect on the epigenome remains unknown. In this study, we investigated the epigenetic landscape of pancreatic cancer cells which harbor the inducible KrasG12D allele. We performed RNA-seq, ChIP-seq against 6 different histone marks, ATAC-seq and RRBS to assess the changes in the epigenome after oncogenic KrasG12D induction.
2021-09-06 | E-MTAB-10896 | biostudies-arrayexpress