Deleting the β-catenin degradation domain in mouse hepatocytes drives hepatocellular carcinoma or hepatoblastoma-like tumor growth

Loesch, Robin; Caruso, Stefano; Paradis, Valérie; Gougelet, Angélique; Renault, Gilles; Picard, Simon; Tanaka, Ingrid; Renoux-Martin, Yoan; Taketo, Makoto Mark; Zucman‐Rossi, Jessica; Colnot, Sabine

doi:10.1016/j.jhep.2022.02.023

Cited by 24 publications

(39 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, we were compelled to investigate the causative relationship between Ctnnb1 aberration and liver tumors in mice. While we and others did not detect liver tumors up to 6 mo after hepatic Ctnnb1 exon 3 deletion ( 9 ), we observed spontaneous tumor formation 11.5 mo after β-catenin activation in mouse liver in this study, similar to a very recent report ( 31 ). Therefore, the reason that previous study did not observe liver tumors caused by Ctnnb1 mutations in mice is due to insufficient observation time.…”

Section: Discussionsupporting

confidence: 90%

Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

Liu

Gai

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

CTNNB1 , encoding β-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated β-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection–mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in β-catenin mutant cell lines and livers. Oncogenic β-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of β-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed β-catenin mutant cell proliferation and tumor formation. Therefore, β-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of β-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for β-catenin mutant liver cancer.

show abstract

Section: Discussionsupporting

confidence: 90%

Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

Liu

Gai

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Importantly, changes in splicing patterns are also induced in FL tissue in DIAMOND mice, in line with recent reports on altered splicing in MAFLD [30][31][32]38]. In combination with the recent data showing that induction of β-catenin activity is sufficient to trigger liver tumorigenesis in mice [7,8], this suggests that altered splicing is a key event that promotes formation of a cellular environment that facilitates malignant transformation in this model. Changes in the expression of genes encoding specific splice factors have been reported to drive tumorigenesis or predispose to malignancy in HCC [15,16,39].…”

Section: Discussionsupporting

confidence: 88%

Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice

López-Pérez

Remeseiro

Hörnblad

2023

Preprint

View full text Add to dashboard Cite

Background & Aims: This study aimed to provide a comprehensive understanding of the regulatory and transcriptional landscape in liver tumours from DIAMOND mice, a mouse model that mimics human hepatocellular carcinoma (HCC) in the context of metabolic associated fatty liver disease (MAFLD). Methods: RNA-sequencing and ChIP-sequencing were used to study the gene expression and regulatory changes in DIAMOND liver tumours. RNA in situ hybridisation splice variant analysis was used to study β-catenin exon 3 exclusion in tumours at cellular resolution. Sequencing data on β-catenin exon 3 splicing in DIAMOND tumours was compared to data from human patients and cell lines. Results: The study found an increase in Wnt/β-catenin-signalling accompanied by rewiring of the Wnt/β-catenin regulatory network in DIAMOND tumours. Changes include switching in the expression of the canonical TCF/LEF downstream effectors and associated chromatin remodelling. In addition, a large subset of DIAMOND tumours showed aberrant splicing of β-catenin, which generate an mRNA isoform that encodes an oncogenic protein. Similar splicing events were found in a fraction of human HCC and hepatoblastoma samples. Conclusions: This study provides evidence that western diet induces aberrant genome-wide splicing in DIAMOND livers, and in particular of the β-catenin gene in a subset of DIAMOND liver tumours. This mechanism is distinct from previously reported activation of β-catenin in HCC and mouse models, since it is independent on mutations in the locus. Our data suggests that metabolic input modulates gene regulatory network responses to active Wnt-signalling, which will be an important consideration also in the human setting. Lay summary: Sequencing data generated in this study highlights the effect of diet in modulating oncogenic gene expression and underscores an alternative mutation-independent mechanism leading to constitutive activation of β-catenin, a well-known driver of liver cancer.

show abstract

“…To study the role of NOMO1 in colorectal carcinogenesis, a conditional Nomo1 mouse model was used to analyze this gene function in a rigorous and specific way that avoids embryonic lethality [ 34 ]. This animal model, which uses the Cre- loxp system to delete a specific gene in a particular tissue, has been efficiently tested by other groups [ 62 , 63 ]. For example, Huang et al used this method to study tumor formation in the colon [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Recurrent NOMO1 Gene Deletion Is a Potential Clinical Marker in Early-Onset Colorectal Cancer and Is Involved in the Regulation of Cell Migration

Pérez-García

Martel-Martel

García-Vallés

et al. 2022

Cancers

View full text Add to dashboard Cite

The incidence of early-onset colorectal cancer (EOCRC; age younger than 50 years) has been progressively increasing over the last decades globally, with causes unexplained. A distinct molecular feature of EOCRC is that compared with cases of late-onset colorectal cancer, in EOCRC cases, there is a higher incidence of Nodal Modulator 1 (NOMO1) somatic deletions. However, the mechanisms of NOMO1 in early-onset colorectal carcinogenesis are currently unknown. In this study, we show that in 30% of EOCRCs with heterozygous deletion of NOMO1, there were pathogenic mutations in this gene, suggesting that NOMO1 can be inactivated by deletion or mutation in EOCRC. To study the role of NOMO1 in EOCRC, CRISPR/cas9 technology was employed to generate NOMO1 knockout HCT-116 (EOCRC) and HS-5 (bone marrow) cell lines. NOMO1 loss in these cell lines did not perturb Nodal pathway signaling nor cell proliferation. Expression microarrays, RNA sequencing, and protein expression analysis by LC–IMS/MS showed that NOMO1 inactivation deregulates other signaling pathways independent of the Nodal pathway, such as epithelial–mesenchymal transition and cell migration. Significantly, NOMO1 loss increased the migration capacity of CRC cells. Additionally, a gut-specific conditional NOMO1 KO mouse model revealed no subsequent tumor development in mice. Overall, these findings suggest that NOMO1 could play a secondary role in early-onset colorectal carcinogenesis because its loss increases the migration capacity of CRC cells. Therefore, further study is warranted to explore other signalling pathways deregulated by NOMO1 loss that may play a significant role in the pathogenesis of the disease.

show abstract

Deleting the β-catenin degradation domain in mouse hepatocytes drives hepatocellular carcinoma or hepatoblastoma-like tumor growth

Cited by 24 publications

References 39 publications

Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice

Recurrent NOMO1 Gene Deletion Is a Potential Clinical Marker in Early-Onset Colorectal Cancer and Is Involved in the Regulation of Cell Migration

Contact Info

Product

Resources

About