RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition

Fang, Lishan; Ford-Roshon, Dane; Russo, Max; O’Brien, Casey; Xiong, Xiaozhe; Gurjao, Carino; Grandclaudon, Maximilien; Raghavan, Srivatsan; Corsello, Steven M.; Carr, Steven A.; Udeshi, Namrata D.; Berstler, James; Sicińska, Ewa; Ng, Kimmie; Giannakis, Marios

doi:10.1038/s41467-022-30794-7

Cited by 36 publications

(29 citation statements)

References 41 publications

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“…Figure 5C shows the detailed list of high-frequency interaction genes in cancer and normal samples. Previous studies demonstrated that abnormal expression of HOXD11 promotes the malignant behavior of glioma cells ( 78 , 79 ). Our results indicate that HOXD11 is a specific high-frequency interaction gene in glioma (Figure 5C ), and there are obvious chromatin interactions between an enhancer enrichment region and the gene HOXD11 in glioma (Figure 5D ).…”

Section: Resultsmentioning

confidence: 99%

ChromLoops: a comprehensive database for specific protein-mediated chromatin loops in diverse organisms

Zhou

Cheng

Zheng

et al. 2022

Nucleic Acids Research

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Chromatin loops (or chromatin interactions) are important elements of chromatin structures. Disruption of chromatin loops is associated with many diseases, such as cancer and polydactyly. A few methods, including ChIA-PET, HiChIP and PLAC-Seq, have been proposed to detect high-resolution, specific protein-mediated chromatin loops. With rapid progress in 3D genomic research, ChIA-PET, HiChIP and PLAC-Seq datasets continue to accumulate, and effective collection and processing for these datasets are urgently needed. Here, we developed a comprehensive, multispecies and specific protein-mediated chromatin loop database (ChromLoops, https://3dgenomics.hzau.edu.cn/chromloops), which integrated 1030 ChIA-PET, HiChIP and PLAC-Seq datasets from 13 species, and documented 1 491 416 813 high-quality chromatin loops. We annotated genes and regions overlapping with chromatin loop anchors with rich functional annotations, such as regulatory elements (enhancers, super-enhancers and silencers), variations (common SNPs, somatic SNPs and eQTLs), and transcription factor binding sites. Moreover, we identified genes with high-frequency chromatin interactions in the collected species. In particular, we identified genes with high-frequency interactions in cancer samples. We hope that ChromLoops will provide a new platform for studying chromatin interaction regulation in relation to biological processes and disease.

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Section: Resultsmentioning

confidence: 99%

ChromLoops: a comprehensive database for specific protein-mediated chromatin loops in diverse organisms

Zhou

Cheng

Zheng

et al. 2022

Nucleic Acids Research

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“…Emerging evidence highlights the pivotal role of RING-type E3 ligases and their substrates in a wide range of human diseases and mutation of RING-type E3s, or modulation of their activity is frequently associated with pathogenesis including viral infections, neurodegenerative disorders, autoimmune diseases and cancer (Cai et al, 2022; Chen et al, 2022; Duan and Pagano, 2021). Indeed, RNF43 mutations have been associated with aggressive tumor biology such as colorectal and endometrial cancer (Fang et al, 2022; Matsumoto et al, 2020; van Herwaarden et al, 2021). To evaluate the impact of other PA-TM-RING E3 ligases in cancer we analyzed TCGA (The Cancer Genome Atlas) tissue mRNA expression data obtained for RNF128, RNF130, RNF167, RNF43 and ZNRF3 from 17 cancer types representing 21 cancer subtypes.…”

Section: Mainmentioning

confidence: 99%

Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR): A Targeted Protein Degradation Toolbox

Siepe

Picton

Garcia

2022

Preprint

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In recent years, targeted protein degradation (TPD) of plasma membrane proteins by hijacking the ubiquitin proteasome system (UPS) or the lysosomal pathway have emerged as novel therapeutic avenues in drug development to address and inhibit canonically difficult targets. While TPD strategies have been successful to target cell surface receptors, these approaches are limited by the availability of suitable binders to generate heterobifunctional molecules. Here, we present the development of a nanobody (VHH) based degradation toolbox termed REULR (Receptor Elimination by E3 Ubiquitin Ligase Recruitment). We generated human and mouse cross-reactive nanobodies against 5 transmembrane PA-TM-RING type E3 Ubiquitin Ligases (RNF218, RNF130, RNF167, RNF43, ZNRF3) covering a broad range and selectivity of tissue expression with which we characterized expression in human and mouse cell lines and immune cells (PBMCs). We demonstrate that heterobifunctional REULR molecules can enforce transmembrane E3 ligase interaction with a variety of disease relevant target receptors (EGFR, EPOR, PD-1) by induced proximity resulting in effective membrane clearance of the target receptor at varying levels. In addition, we designed E3 Ligase self-degrading molecules, "fratricide" REULRs (RNF128, RNF130, RENF167, RNF43, ZNRF3), that allow downregulation of one or several E3 Ligases from the cell surface and consequently modulate receptor signaling strength. REULR molecules represent a VHH-based, modular and versatile "mix and match" targeting strategy for facile modulation of cell surface proteins by induced proximity to transmembrane PA-TM-RING E3 ligases.

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“…While we reveal a key role of adjustable WNT signalling for TINC formation and BRAF / RNF43 -mutant tumour survival and growth, additional pathways may play a role. RNF43 truncating mutations were recently linked to activation of the PI3K-Akt-mTOR pathway 37 , which also mediates activation of cellular programs linked to glycolysis and hypoxia 38 , as well as Goblet and Paneth cell differentiation in the mouse intestine and human intestinal organoids 22,23,39,40 . Our findings further indicate that the cancer driver activity of WNT mutations relies on a specific mutational context.…”

Section: Mainmentioning

confidence: 99%

RNF43 mutations facilitate colorectal cancer metastasis via formation of a tumour-intrinsic niche

Bugter

Bouazzaoui

Küçükköse

et al. 2022

Preprint

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Colorectal cancer (CRC) develops via two mutually exclusive genetic pathways that involve distinct WNT pathway alterations. Downstream APC mutations initiate development of conventional WNT-high adenocarcinomas. By contrast, RNF43 mutations induce hypersensitivity to WNTs at the receptor level and are mainly found in BRAF V600E-initiated serrated adenomas that advance into WNT-low mucinous adenocarcinomas with poor prognosis upon metastasis. How RNF43 mutations contribute to tumour progression remains unclear. Here, we employed gene editing to repair RNF43 mutations in patient-derived CRC organoids. In comparison to their RNF43-mutant counterparts, RNF43-corrected CRC organoids display a diminished mucinous phenotype, loss of niche factor independency and loss of metastatic capacity upon orthotopic transplantation in mice. Mechanistically, mutant RNF43 promotes formation of a non-dividing secretory cell population that secretes essential growth factors and provide a state of self-sufficiency to the cancer epithelium. Unlike APC mutations, we show that RNF43-mutations provide tuneable WNT levels that permits the formation of these niche-like cells in parallel to proliferative WNT-high cancer cells. Also in patient samples, formation of these tumour-intrinsic niche cells (TINCs) correlate with RNF43-mutant CRC, mucinous histology and metastatic capacity and represents a cellular mechanism by which tumours acquire self-sufficiency.

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RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition

Cited by 36 publications

References 41 publications

ChromLoops: a comprehensive database for specific protein-mediated chromatin loops in diverse organisms

ChromLoops: a comprehensive database for specific protein-mediated chromatin loops in diverse organisms

Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR): A Targeted Protein Degradation Toolbox

RNF43 mutations facilitate colorectal cancer metastasis via formation of a tumour-intrinsic niche

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