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Signaling Response to Early Oncogenesis by a Novel Panel of Murine Mutant Kras Alleles in the Mouse Lung Transcriptome [I]

ABSTRACT: Despite over 50 oncogenic RAS mutations, specific mutations track with distinct cancer types. To elucidate the underlying contribution of oncogenic signaling to RAS mutation patterns we globally activated a novel panel of endogenous murine Kras alleles with biochemically distinct mutations encoded with native or common codons producing low or high protein levels. Each induced unique tumor patterns, with quantitative signaling favoring hematopoietic tumors, qualitative signaling favoring squamous tumors, while carcinomas tended to be a combination of both types of signaling. Mechanistically, these mutants generated very different levels of active Kras and cellular responses, with low Kras activity yielding transcriptional features of a multipotent state while high activity had all the hallmarks of potent oncogenic activity and resultant stress and an inflammatory response. We thus suggest that the RAS mutational bias to specific cancer types is a result of tissue-specific responses of normal cells to either or both quantitative and qualitative signaling differences imparted by the selected mutant.

ORGANISM(S): Mus musculus

PROVIDER: GSE181627 | GEO | 2021/08/09

REPOSITORIES: GEO

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Signaling Response to Early Oncogenesis by a Novel Panel of Murine Mutant Kras Alleles in the Mouse Lung Transcriptome [II]

Project description:Despite over 50 oncogenic RAS mutations, specific mutations track with distinct cancer types. To elucidate the underlying contribution of oncogenic signaling to RAS mutation patterns we globally activated a novel panel of endogenous murine Kras alleles with biochemically distinct mutations encoded with native or common codons producing low or high protein levels. Each induced unique tumor patterns, with quantitative signaling favoring hematopoietic tumors, qualitative signaling favoring squamous tumors, while carcinomas tended to be a combination of both types of signaling. Mechanistically, these mutants generated very different levels of active Kras and cellular responses, with low Kras activity yielding transcriptional features of a multipotent state while high activity had all the hallmarks of potent oncogenic activity and resultant stress and an inflammatory response. We thus suggest that the RAS mutational bias to specific cancer types is a result of tissue-specific responses of normal cells to either or both quantitative and qualitative signaling differences imparted by the selected mutant.

2021-08-09 | GSE181628 | GEO

GSK-3alpha Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1-TAB Stabilization and Regulation of Non-Canonical NF-kB

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

Defective K-Ras Oncoproteins Initiate Cancer In Vivo and Evolve to Overcome Impaired Effector Binding

Project description:The oncogenic proteins expressed in human cancer cells are exceedingly difficult targets for drug discovery due to intrinsic properties of the Ras GTPase switch. As a result, recent efforts have largely focused on inhibiting Ras-regulated kinase effector cascades, particularly the Raf/MEK/ERK and PI3 kinase/Akt/mTOR pathways. We constructed murine stem cell leukemia virus (MSCV) vectors encoding oncogenic K-RasD12 with additional “second site” amino acid substitutions that that impair PI3 kinase/Akt or Raf/MEK/ERK activation and performed bone marrow transduction/transplantation experiments in mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins induced aggressive clonal T lineage acute lymphoblastic leukemia (T-ALL). These leukemias exhibited a high frequency of somatic Notch1 mutations, which is also true of human T-ALL. Multiple independent T-ALLs restored full oncogenic Ras activity by acquiring “third site” mutations within the viral KrasD12 transgenes. Other leukemias with undetectable PTEN and elevated phosphoryated Akt levels showed a similar gene expression profile to human early T progenitor (ETP) T-ALL. Expressing oncoproteins that are defective for specific functions is a general strategy for assessing requirements for tumor maintenance and uncovering potential mechanisms of drug resistance in vivo. In addition, our observation that defective Kras oncogenes regain potent cancer initiating activity strongly supports simultaneously targeting distinct components of Ras signaling networks in the substantial fraction of cancers with RAS mutations. WT Balb/c mice were lethally irradiated and transplanted with WT Balb/c bone marrow cells transduced with MSCV-IRES-Kras mutant-GFP vectors. Mice developed T-cell lymphoproliferative disease.

2011-09-30 | E-GEOD-28687 | biostudies-arrayexpress

Oncogenic potential of RAS isoforms in melanocytes

Project description:We compared the transformation efficiencies of mutant NRAS and KRAS in immortal, non-transformed Ink4a/Arf-deficient melanocytes. NRAS mutation leads to increased cellular proliferation and is potently tumorigenic. In contrast, KRAS mutation does not enhance melanocyte proliferation and is only weakly tumorigenic on its own. While both NRAS and KRAS activate MAPK signaling, only NRAS enhances MYC activity in these cells. Our data suggests that the activity of specific RAS isoforms is context dependent and provides a possible explanation for the prevalence of NRAS mutations in melanoma.In addition, understanding this mechanism will have important implications for cancer therapies targeting RAS pathways. Keywords: RAS isoforms Common Reference

2010-06-10 | E-GEOD-6194 | biostudies-arrayexpress

GSK-3alpha Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1-TAB Stabilization and Regulation of Non-Canonical NF-kB

2013-05-31 | GSE42559 | GEO

Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer

Project description:Oncogenic KRAS mutations are a key driver for initiation and progression in non-small-cell lung cancer (NSCLC). However, how post-translational modifications (PTMs) of KRAS, especially methylation, modify KRAS activity remain largely unclear. Here, we show that SET domain containing histone lysine methyltransferase 7 (SETD7) interacts with KRAS and methylates KRAS at lysines 182 and 184. SETD7-mediated methylation of KRAS leads to degradation of KRAS and attenuation of the RAS/MEK/ERK signaling cascade, endowing SETD7 with a potent tumor-suppressive role in NSCLC, both in vitro and in vivo. Mechanistically, RABGEF1, a ubiquitin E3 ligase of KRAS, was recruited and promoted KRAS degradation in a K182/K184 methylation-dependent manner. Notably, SETD7 is inversely correlated with KRAS at the protein level in clinical NSCLC tissues. Low SETD7 or RABGEF1 expression is associated with poor prognosis in lung adenocarcinoma patients. Altogether, our results elucidate a tumor-suppressive function of SETD7 that operates via modulating KRAS methylation and degradation.

2023-07-19 | PXD043931 | iProX

Transcriptomic profiling identifies unique and shared functions of oncogenic KRAS and RIT1

Project description:Aberrant activation of RAS oncogenes is a prevalent event in lung adenocarcinoma, with somatic mutation of KRAS occurring in ~30% of tumors. Recently, we identified somatic mutation of the RAS-family GTPase RIT1 in lung adenocarcinoma, but relatively little is known about the biological pathways regulated by RIT1 and how these relate to the oncogenic KRAS network. Here we present (quantitative proteomic and) transcriptomic profiles from KRAS-mutant and RIT1-mutant isogenic lung epithelial cells and globally characterize the signaling networks regulated by each oncogene.

2020-03-06 | GSE146479 | GEO

Less invasive diagnostics for identification and monitoring of cancer associated mutations in blood

Project description:Primary outcome(s): Quantitative detection and monitoring of genetic mutations in tumor-associated genes, such as oncogenic KRAS, in circulating plasma DNA.

| 2628163 | ecrin-mdr-crc

KRAS and YAP1 converge to regulate EMT and tumor survival

Project description:Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival in the setting of KRAS suppression. In this model, the transcriptional co-activator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling Three biological replicates of primary lung adenocarcinoma cells derived from the Kras Lox-STOP-Lox-G12D;p53flox/flox (KP) mouse lung cancer model into which a doxycycline-inducible shRNA targeting Kras expressed from the 3’UTR of GFP was introduced (KP-KrasA cells) were analyzed at timepoints (days) D0, D4, and D21.

2014-07-27 | E-GEOD-56175 | biostudies-arrayexpress

Defective K-Ras Oncoproteins Initiate Cancer In Vivo and Evolve to Overcome Impaired Effector Binding

2011-10-01 | GSE28687 | GEO

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