Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc-finger genes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE120566 | GEO | 2022/07/19
REPOSITORIES: GEO
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Project description:Lo A, Holmes K, Mundt F, Moorthi S, Fung I, Fereshetian S, Watson J, Carr SA, Mertins P, Berger A. 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. We find that both mutant KRAS and mutant RIT1 promote S6 kinase, AKT, and RAF/MEK signaling, and promote epithelial-to-mesenchymal transition and immune evasion via HLA protein loss. However, KRAS and RIT1 diverge in regulation of phosphoproteins including EGFR, USO1, and AHNAK proteins. The majority of the proteome changes are related to altered transcriptional regulation, but a small subset of proteins are differentially regulated at the post-transcriptional level, including intermediate filament proteins, metallothioneins, and MHC Class I proteins, which are profoundly suppressed by oncogenic KRAS and RIT1 variants. These data provide the first global, unbiased characterization of oncogenic RIT1 network and identify the shared and divergent functions of oncogenic RIT1 and KRAS GTPases in lung cancer.
2020-04-03 | MSV000085225 | MassIVE
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
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
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
2014-07-27 | GSE56175 | GEO
Project description:The highest frequencies of KRAS mutations occur in colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC). Therapeutically targeting downstream pathways mediating oncogenic properties of KRAS mutant cancers is limited by an incomplete understanding of the contextual cues modulating the signaling output of activated KRAS. We performed mass spectrometry on mouse tissues expressing wild-type or mutant KRAS to determine how tissue context and genetic background modulate oncogenic signaling. Mutant KRAS dramatically altered the proteomes and phosphoproteomes of pre-neoplastic and neoplastic colons and pancreases in a largely context-specific manner. We developed an approach to humanize the mouse networks with data from human cancer and identified genes within the CRC and PDAC networks synthetically lethal with mutant KRAS. Our studies demonstrate the context-dependent plasticity of oncogenic signaling, identify non-canonical mediators of KRAS oncogenicity within the KRAS-regulated signaling network, and demonstrate how statistical integration of mouse and human datasets can reveal cross-species therapeutic insights.
2019-06-28 | PXD013922 | Pride
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. We used microarrays to compare gene expression in HCT116 cells in which we suppressed KRAS expression doxycycline-inducible shRNA targeting KRAS compared to cells treated with media alone (no shKRAS induced). We express KRAS, LacZ, and YAP1 in each condition to identify genes transcriptionally involved in the rescue of KRAS suppression. HCT116 cells harboring doxycycline-inducible shKRAS (HCTtetK) expressing either LacZ, KRAS, or YAP1, were treated with doxycycline for 30 hours to suppress KRAS. Untreated (no doxycycline) cells expressing each ORF were used as control. Total RNA was collected using PerfectPure RNA Cultured Cell Kit (5Prime) and expression profiling was performed on Human Genome U133A 2.0 Array (Affymetrix) using the Dana Farber Cancer Institute Microarray Core.
2014-07-22 | E-GEOD-55942 | biostudies-arrayexpress
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
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 | GSE181627 | GEO
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. We used microarrays to compare gene expression in HCT116 cells in which we suppressed KRAS expression doxycycline-inducible shRNA targeting KRAS compared to cells treated with media alone (no shKRAS induced). We express KRAS, LacZ, and YAP1 in each condition to identify genes transcriptionally involved in the rescue of KRAS suppression.
2014-07-22 | GSE55942 | GEO
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