Cooperativity between Ras pathway mutations in colonic tumorigenesis
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ABSTRACT:
PROVIDER: PRJNA1281551 | ENA |
REPOSITORIES: ENA
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Project description:The Kirsten rat sarcoma (KRAS) gene is the most frequently mutated oncogene in colorectal cancer (CRC). We previously characterized two activating alleles of KRAS, A59T and A59E, that show impaired BRAF dimerization. These alleles of KRAS are enriched in CRC tumors with genetic alterations in genes that regulate MAPK signaling (e.g. EGFR, NF1). Using a new conditional mouse model of K-Ras (LSL-K-Ras A59E) we show that, despite its inability to universally activate RAF kinases, K-Ras A59E disturbs colon epithelium and decreases mouse survival in a tumor model. By combining LSL-K-Ras A59E mice with a conditional knockout of Nf1, we demonstrate cooperation between these alleles at multiple levels. Consistent with cooperation and clinical observations, we show that K-Ras A59E neither promotes EGF independence of organoid growth, nor confers intrinsic resistance to EGFR inhibition. Thus, our data provide a deeper understanding of the role of RAF isoforms in mutant KRAS driven CRC and argue for the use of anti-EGFR therapies against some Ala59 mutant alleles of KRAS.
2025-07-02 | GSE300614 | GEO
Project description:K-Ras is frequently hyperactivated in human cancers through gain-of-function mutations that drive tumorigenesis. K-RasG12D, the most common oncogenic K-Ras allele, triggers massive transcriptomic and proteomic changes in the murine colon. Here, we report a comprehensive profile of physiological miRNA targets in murine colonic epithelium and tumor expressing K-RasG12D. Combining it with transcriptional, transcriptomic, and proteomic landscapes, we uncover a K-RasG12D-induced global suppression of miRNA activity that up-regulates hundreds of genes post-transcriptionally. K-RasG12D suppresses Csnk1a1 and Csnk2a1, which can decrease Ago2 phosphorylation at Ser825/829/831/835. Hypo-phosphorylated Ago2 increases binding with mRNA, reducing its regulatory activity by locking Ago2 in a small set of target transcripts. While expanding the repertoire of miRNA targets identified, it functionally decreases active Ago2, resulting in global de-repression of miRNA targets. Our findings establish a regulatory relationship among K-Ras, Csnk1a1/Csnk2a1, and Ago2 that provides a mechanistic link between oncogenic K-Ras and the up-regulation of hundreds of miRNA targets.
2022-05-13 | GSE189704 | GEO
Project description:K-Ras is frequently hyperactivated in human cancers through gain-of-function mutations that drive tumorigenesis. K-RasG12D, the most common oncogenic K-Ras allele, triggers massive transcriptomic and proteomic changes in the murine colon. Here, we report a comprehensive profile of physiological miRNA targets in murine colonic epithelium and tumor expressing K-RasG12D. Combining it with transcriptional, transcriptomic, and proteomic landscapes, we uncover a K-RasG12D-induced global suppression of miRNA activity that up-regulates hundreds of genes post-transcriptionally. K-RasG12D suppresses Csnk1a1 and Csnk2a1, which can decrease Ago2 phosphorylation at Ser825/829/831/835. Hypo-phosphorylated Ago2 increases binding with mRNA, reducing its regulatory activity by locking Ago2 in a small set of target transcripts. While expanding the repertoire of miRNA targets identified, it functionally decreases active Ago2, resulting in global de-repression of miRNA targets. Our findings establish a regulatory relationship among K-Ras, Csnk1a1/Csnk2a1, and Ago2 that provides a mechanistic link between oncogenic K-Ras and the up-regulation of hundreds of miRNA targets.
2022-05-13 | GSE189702 | GEO
Project description:K-Ras is frequently hyperactivated in human cancers through gain-of-function mutations that drive tumorigenesis. K-RasG12D, the most common oncogenic K-Ras allele, triggers massive transcriptomic and proteomic changes in the murine colon. Here, we report a comprehensive profile of physiological miRNA targets in murine colonic epithelium and tumor expressing K-RasG12D. Combining it with transcriptional, transcriptomic, and proteomic landscapes, we uncover a K-RasG12D-induced global suppression of miRNA activity that up-regulates hundreds of genes post-transcriptionally. K-RasG12D suppresses Csnk1a1 and Csnk2a1, which can decrease Ago2 phosphorylation at Ser825/829/831/835. Hypo-phosphorylated Ago2 increases binding with mRNA, reducing its regulatory activity by locking Ago2 in a small set of target transcripts. While expanding the repertoire of miRNA targets identified, it functionally decreases active Ago2, resulting in global de-repression of miRNA targets. Our findings establish a regulatory relationship among K-Ras, Csnk1a1/Csnk2a1, and Ago2 that provides a mechanistic link between oncogenic K-Ras and the up-regulation of hundreds of miRNA targets.
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Project description:Ephexin1 was initially identified as a neuronal guanine nucleotide exchange factor involved in the control of neuronal development and synaptic homeostasis. Here, we demonstrate that the induction of Ephexin1 expression by an oncogenic K-Ras mutation amplifies the MAPK signaling via direct interaction with oncogenic Ras and contributes to colon and lung tumorigenesis. Ephexin1 cooperates with mutant Ras to accelerate skin tumorigenesis in vivo. In addition, we have demonstrated that the functionally relevant interaction between oncogenic K-Ras and Ephexin1. Together, these findings suggest that Ephexin1 serves as a positive regulator of Ras-driven oncogenesis and potentially represents a novel target for therapeutic intervention.
2021-10-27 | GSE147809 | GEO
Project description:K-Ras is frequently hyperactivated in human cancers through gain-of-function mutations that drive tumorigenesis. K-RasG12D, the most common oncogenic K-Ras allele, triggers massive transcriptomic and proteomic changes in the murine colon. Here, we report a comprehensive profile of physiological miRNA targets in murine colonic epithelium and tumor expressing K-RasG12D. Combining it with transcriptional, transcriptomic, and proteomic landscapes, we uncover a K-RasG12D-induced global suppression of miRNA activity that up-regulates hundreds of genes post-transcriptionally. K-RasG12D suppresses Csnk1a1 and Csnk2a1, which can decrease Ago2 phosphorylation at Ser825/829/831/835. Hypo-phosphorylated Ago2 increases binding with mRNA, reducing its regulatory activity by locking Ago2 in a small set of target transcripts. While expanding the repertoire of miRNA targets identified, it functionally decreases active Ago2, resulting in global de-repression of miRNA targets. Our findings establish a regulatory relationship among K-Ras, Csnk1a1/Csnk2a1, and Ago2 that provides a mechanistic link between oncogenic K-Ras and the up-regulation of hundreds of miRNA targets.
2022-05-13 | GSE189701 | GEO
Project description:K-Ras is frequently hyperactivated in human cancers through gain-of-function mutations that drive tumorigenesis. K-RasG12D, the most common oncogenic K-Ras allele, triggers massive transcriptomic and proteomic changes in the murine colon. Here, we report a comprehensive profile of physiological miRNA targets in murine colonic epithelium and tumor expressing K-RasG12D. Combining it with transcriptional, transcriptomic, and proteomic landscapes, we uncover a K-RasG12D-induced global suppression of miRNA activity that up-regulates hundreds of genes post-transcriptionally. K-RasG12D suppresses Csnk1a1 and Csnk2a1, which can decrease Ago2 phosphorylation at Ser825/829/831/835. Hypo-phosphorylated Ago2 increases binding with mRNA, reducing its regulatory activity by locking Ago2 in a small set of target transcripts. While expanding the repertoire of miRNA targets identified, it functionally decreases active Ago2, resulting in global de-repression of miRNA targets. Our findings establish a regulatory relationship among K-Ras, Csnk1a1/Csnk2a1, and Ago2 that provides a mechanistic link between oncogenic K-Ras and the up-regulation of hundreds of miRNA targets.
2022-05-13 | GSE189700 | GEO
Project description:Ephexin1 cooperates with K-Ras to promote oncogenic Ras-driven tumorigenesis
| PRJNA619876 | ENA
Project description:-7/del(7q) is genetic event prevalent in high-risk myeloid neoplasms. For reasons that are unclear, gain-of-function mutations in the RAS pathway frequently co-occur with monosomy 7. Here we identify a genetic interaction between RAS and the 7q-encoded transcription factor, CUX1. Concomitant mutations in RAS genes and CUX1 are wide-spread across tumor types, suggesting cooperativity in tumorigenesis. To test this, we generated mice with oncogenic NrasG12D and Cux1 knockdown. Double mutant mice developed myeloid malignancies with higher penetrance and faster onset than either single allele alone, with leukemic transformation in one third of cases. Oncogenic RAS imparts increased self-renewal on CUX1-deficient hematopoietic stem and progenitor cells (HSPCs). Reciprocally, CUX1 knockdown amplifies RAS signaling through decreased transcriptional expression of negative regulators of RAS and PI3K signaling. Accordingly, NrasG12D;Cux1-knockdown HSPCs have heighted growth factor-sensitivity and downstream RAS pathway activation. Double mutant HSPCs were responsive to PIK3 or MEK inhibition, suggesting that these may be promising therapeutic targets in patients with 7/del(7q) malignancies. Our results implicate the loss of CUX1 as the underlying explanation for the association of -7/del(7q) with oncogenic RAS. Furthermore, we report the unexpected convergence of an oncogene and tumor suppressor gene on the same pathway.
2021-11-16 | GSE161614 | GEO
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| PRJNA453686 | ENA