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RNA-seq profiles of Tp53, Prkar1a and Axin1 edited basal organoids from a mouse model of breast cancer

ABSTRACT: This study demonstrates the applicability of an in vivo CRISPR/Cas9 genome-wide screen in the BALB/c-Trp53+/– mouse model of breast cancer to identify novel tumor suppressor genes involved in mammary tumorigenesis. Preneoplastic mammary organoids were established from using sorted basal cells isolated from BALB/c-Trp53+/– mice. CRISPR/Cas9 screening was used to target Trp53, Axin1 and Prkar1a. To explore the potential molecular basis of the morphological differences, RNA-seq analysis was used to compare the Axin1/Trp53 and Prkar1a/Trp53-edited organoids and to organoids targeted by Trp53-only guides.

ORGANISM(S): Mus musculus

PROVIDER: GSE184070 | GEO | 2021/12/21

REPOSITORIES: GEO

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MEK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis [RNASeq_HCT116]

Project description:AXIN1 is a central regulatory hub of many oncogenic pathways in colorectal cancer (CRC). As the main scaffold protein and least abundant component of the beta-catenin destruction complex, changes in AXIN1 levels affect Wnt signaling output. We show that targeting the Ras-MAPK pathway by MEK1/2 inhibitors induces AXIN1 loss across a panel of CRC cell lines and patient-derived organoids. GSK3B inhibition similarly reduced AXIN1 levels, yet by distinct mechanisms. MEK1/2 causes a reduction of AXIN1 transcript levels, but neither affects protein stability nor post-translational modifications of AXIN1. In contrast, GSK3B inhibition induces rapid AXIN1 degradation. Prevention of AXIN1 loss by co-treatment with tankyrase inhibitors was much stronger for GSK3B than for MEK1/2 inhibition. Using isogenic CRC cell lines and murine intestinal organoids, we show that APC truncations strongly reduce basal AXIN1 levels, but do not alter dynamics of AXIN1 loss upon MEK1/2 inhibition. Polysome profiling and Ribo-Seq revealed that MEK1/2 inhibition reduces global protein synthesis via an mTOR dependent pathway. This translational repression is sufficient to cause significant AXIN1 loss, as treatment with mTOR inhibitors phenocopies the effect of MEK1/2 inhibitors. Our study demonstrates that AXIN1 protein homeostasis is critically controlled by Ras-MAPK signaling at the level of protein synthesis, and that MEK1/2 inhibitors cause AXIN1 loss by translational repression.

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MEK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis [RiboSeq_HCT116]

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Expression alterations induced by restoration of AXIN1 expression in SNU449 hepatocellular carcinoma cells

Project description:Aberrant activation of Wnt/β-catenin signaling is observed in numerous cancers. In hepatocellular carcinoma activating mutations in CTNNB1 (20-25%) or loss of function mutations in AXIN1 (10%), AXIN2 (2%) and APC (1-2%) are observed. All these mutations lead to aberrant stabilization of β-catenin, which constitutively activates downstream Wnt/β-catenin target genes and triggers a genetic program resulting in tumor formation. However, in relation to AXIN1 mutations some reports have challenged whether these indeed result in tumor growth by enhancing β-catenin signaling (e.g. PMID: 16964294, 29525529). Several alternative pathways have also been linked to AXIN1 (ENSG00000103126), such as TGFβ, SAPK/JNK, p53, YAP/TAZ and c-myc. To identify which one of these or other unknown signaling routes are linked to AXIN1, using CRISPR-Cas9 genome editing, we have successfully repaired the homozygous p.R712* AXIN1 mutation present in the SNU449 hepatocellular carcinoma cell line. Next, using RNA sequencing the RNA expression patterns of 3 independent repaired clones were compared with 3 clones retaining the AXIN1 mutation. Surprisingly, only 5 genes were significantly altered in the repaired clones, among which AXIN2, a well-established β-catenin target gene. Thus, this analysis leads to the surprising observation that a commonly observed mutation in a hepatocellular tumor suppressor gene, is associated with minimal alterations in gene expression, at least in the SNU449 cell line.

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CRISPR/Cas9 repaired AXIN1-mutant liver cancer cell lines

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RNA-seq profiles of Tp53, Prkar1a and Axin1 edited basal organoids from a mouse model of breast cancer

Project description:RNA-seq profiles of Tp53, Prkar1a and Axin1 edited basal organoids from a mouse model of breast cancer

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Breast Cancer Suppressor Role of RUNX1: Estrogen-dependent Regulation of AXIN1 and b-catenin

Project description:The transcription factor RUNX1 exhibits recurrent loss-of-function mutations in estrogen receptor-positive (ER+) breast cancer (BCa). Its knockdown in vitro decreased AXIN1 expression in estrogen-dependent manner. Consistently, RUNX1 and AXIN1 mRNA levels are strongly correlated in ER+, not ER- tumors. RUNX1 occupies AXIN1â??s second intron in living cells, abutting an ERa-binding site. Potentially promoting BCa progression, decreased AXIN1 expression after RUNX1 knockdown associated with upregulation of b-catenin, and this was preventable by AXIN stabilizers. Unlike in colon cancer, however, deregulation of b-catenin in BCa cells affect neither c-Myc, nor CCND1, nor G1/S cell cycle phase transition. Instead, cyclin B1 was decreased and the G2/M checkpoint was compromised as indicated by mitotic slippage in the presence of microtubule disruptors. Thus, combined analysis of the RUNX1 transcriptome, its cistrome, and differential mRNA expression in tumors with wild type versus mutant RUNX1, altogether highlight a role for the RUNX1/AXIN1/b-catenin axis in ER+ BCa. Significance: Three recent exome sequencing studies assigned to RUNX1 a BCa suppressor role. The present study begins to uncover the underlying molecular mechanisms, offers an explanation for the specificity to ER+ tumors, and marks AXIN1 as a therapeutic target for ER+/RUNX1- BCa. Examination of RUNX1 binding in MCF7 cells

2016-02-22 | E-GEOD-65313 | biostudies-arrayexpress

Gene expression in homozygous mbl/axin1 zebrafish

Project description:Homozygous masterblind (mbl-/-) zebrafish exhibit reduced or absent eyes and telecephalon, and the expansion of the diencephalic fates to the front of the brain. A missense mutation in the GSK3-binding domain of zebrafish axin1, a scaffolding protein in the Wnt signaling pathway, results in the mbl phenotype. In an effort to identify and study the genes affected by Wnt signaling, we used a 14,000-oligonucleotide-gene microarray to determine differentially expressed genes in mbl/axin1 (-/-) and wild type control zebrafish embryos and larvae. Keywords: zebrafish, Danio rerio, wild-type mbl, axin1, development

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Prkar1a haploinsufficiency leads to an overall increase in tumors caused by other genetic defects or chemical induction

Project description:[original title] Prkar1a haploinsufficiency in mice leads to an overall increase in tumors caused by other genetic defects or chemical induction We investigated the Prkar1a+/- mice when bred within the Rb1+/- or Trp53+/- genetic backgrounds, or treated with a 2-step skin carcinogenesis protocol. Prkar1a+/-Trp53+/- mice developed more bone sarcomas than Trp53+/- mice (p<0.05) and Prkar1a+/-Rb1+/- mice grew more and larger pituitary and thyroid tumors than Rb1+/- mice. All mice with double heterozygosity had significantly reduced life-spans compared with their single-heterozygous counterparts. Finally, Prkar1a+/- mice developed more papillomas than wild-type animals when treated with a 2-step skin carcinogenesis protocol. A whole-genome transcriptome profiling of tumors produced by all three models identified Wnt signaling as the main pathway activated by abnormal cAMP signaling in these tissues, along with (expected) cell cycle gene abnormalities, all confirmed by qRT-PCR array and immunohistochemical analyses.

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Ras-MAPK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis.

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