The Wnt pathway-antagonising tumor suppressor RNF43 is frequently lost in human malignancies. Identification of a distinct class of patient-derived RNF43 truncating mutations that drive Wnt receptor/β-catenin target expression in a ligand-independent manner may impact on current cancer treatment schemes.

• Expression of C-terminally-truncated RNF43 increases β-catenin-mediated transcription in the absence of Wnt ligands.
• Truncated RNF43 retains destruction complex components CK1 and AXIN at the plasma membrane.
• CK1α-mediated phosphorylation of the cytosolic tail of truncated RNF43 activates intracellular Wnt signaling.
• Oncogenic RNF43 induces TP53-dependent epithelial growth arrest in human colon organoids, and decreases sensitivity to anti-Wnt-based therapy.

Abstract

Wnt/β-catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt-hypersensitive tumors that are susceptible to anti-Wnt-based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce β-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a ubiquitin-independent suppressor role of the RNF43 cytosolic tail that involves Casein kinase 1 (CK1) binding and phosphorylation. Mechanistically, truncated RNF43 variants trap CK1 at the plasma membrane, thereby preventing β-catenin turnover and propelling ligand-independent target gene transcription. Gene editing of human colon stem cells shows that RNF43 truncations cooperate with p53 loss to drive a niche-independent program for self-renewal and proliferation. Moreover, these RNF43 variants confer decreased sensitivity to anti-Wnt-based therapy. Our data demonstrate the relevance of studying patient-derived mutations for understanding disease mechanisms and improved applications of precision medicine.

Nat Commun. 2022; 13: 334.

Published online 2022 Jan 17. doi: 10.1038/s41467-021-27923-z

PMCID: PMC8764073

PMID: 35039505

RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state

Germán Belenguer,#1 Gianmarco Mastrogiovanni,#2,3,4 Clare Pacini,#5 Zoe Hall,6 Anna M. Dowbaj,1 Robert Arnes-Benito,1 Aleksandra Sljukic,1 Nicole Prior,1 Sofia Kakava,1 Charles R. Bradshaw,2 Susan Davies,7 Michele Vacca,8,9 Kourosh Saeb-Parsy,10 Bon-Kyoung Koo,11 and Meritxell Huch1,2,3

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Abstract

RNF43/ZNRF3 negatively regulate WNT signalling. Both genes are mutated in several types of cancers, however, their contribution to liver disease is unknown. Here we describe that hepatocyte-specific loss of Rnf43/Znrf3 results in steatohepatitis and in increase in unsaturated lipids, in the absence of dietary fat supplementation. Upon injury, Rnf43/Znrf3 deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. Using hepatocyte-, hepatoblast- and ductal cell-derived organoids we demonstrate that the differentiation defects and lipid alterations are, in part, cell-autonomous. Interestingly, ZNRF3 mutant liver cancer patients present poorer prognosis, altered hepatic lipid metabolism and steatohepatitis/NASH signatures. Our results imply that RNF43/ZNRF3 predispose to liver cancer by controlling the proliferative/differentiation and lipid metabolic state of hepatocytes. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 mutated individuals at risk of developing fatty liver and/or liver cancer.

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• ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner.[Nature. 2012]
• Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors.[Nature. 2012]
• Review The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength.[Genes Dev. 2014]
• Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways.[Proc Natl Acad Sci U S A. 2011]
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See more ...

• ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation.[Cell Stem Cell. 2021]

• Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors.[Nature. 2012]
• The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size.[Nat Cell Biol. 2016]
• Efficient temporally controlled targeted somatic mutagenesis in hepatocytes of the mouse.[Genesis. 2004]

• Apc tumor suppressor gene is the "zonation-keeper" of mouse liver.[Dev Cell. 2006]
• Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis.[J Hepatol. 2008]
• Treatment of Nonalcoholic Fatty Liver Disease.[Curr Treat Options Gastroenterol. 2003]
• Design and validation of a histological scoring system for nonalcoholic fatty liver disease.[Hepatology. 2005]

• PohnB6F1: a cross of wild and domestic mice that is a new model of extended female reproductive life span.[J Gerontol A Biol Sci Med Sci. 2007]

• The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size.[Nat Cell Biol. 2016]
• Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand.[Cell. 2012]

• Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand.[Cell. 2012]

• Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease.[Hepatology. 2017]

• Lgr5⁺ stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool.[Development. 2019]
• Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids.[Cell. 2018]

• Elovl6 promotes nonalcoholic steatohepatitis.[Hepatology. 2012]
• Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer.[Cell. 2015]

• Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver.[Gastroenterology. 2005]
• Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas.[Proc Natl Acad Sci U S A. 2004]

• Multilineage communication regulates human liver bud development from pluripotency.[Nature. 2017]
• A single-cell transcriptomic analysis reveals precise pathways and regulatory mechanisms underlying hepatoblast differentiation.[Hepatology. 2017]
• Review Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.[Am J Pathol. 2010]

• Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids.[Cell. 2018]
• Lgr5⁺ stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool.[Development. 2019]
• In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration.[Nature. 2013]
• Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells.[Nat Cell Biol. 2011]
• The effect of ICRT-3 on Wnt signaling pathway in head and neck cancer.[J Cell Biochem. 2019]

• Human primary liver cancer-derived organoid cultures for disease modeling and drug screening.[Nat Med. 2017]

• Focal gains of VEGFA and molecular classification of hepatocellular carcinoma.[Cancer Res. 2008]
• Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.[Cancer Cell. 2008]
• Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids.[Hepatology. 2015]

• International network of cancer genome projects.[Nature. 2010]
• International Cancer Genome Consortium Data Portal--a one-stop shop for cancer genomics data.[Database (Oxford). 2011]
• Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.[Nat Genet. 2015]

• Human primary liver cancer-derived organoid cultures for disease modeling and drug screening.[Nat Med. 2017]

• Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.[Nat Genet. 2015]
• Exome sequencing of liver fluke-associated cholangiocarcinoma.[Nat Genet. 2012]
• Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.[Nat Genet. 2012]
• Review Dynamics of cancer progression.[Nat Rev Cancer. 2004]

• Review The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue.[Cell Metab. 2014]
• Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a.[FASEB J. 2015]
• Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas.[Proc Natl Acad Sci U S A. 2004]
• Evidence that fold-change, and not absolute level, of beta-catenin dictates Wnt signaling.[Mol Cell. 2009]
• The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse.[Cell Stem Cell. 2011]
• Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.[Nat Cell Biol. 2010]
• ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation.[Cell Stem Cell. 2021]

• Elovl6 promotes nonalcoholic steatohepatitis.[Hepatology. 2012]
• Review Animal models of non-alcoholic fatty liver disease: current perspectives and recent advances.[J Pathol. 2017]
• ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation.[Cell Stem Cell. 2021]

• Loss of RNF43 Function Contributes to Gastric Carcinogenesis by Impairing DNA Damage Response.[Cell Mol Gastroenterol Hepatol. 2021]
• Review Role of non-coding sequence variants in cancer.[Nat Rev Genet. 2016]
• RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer.[EMBO J. 2020]
• A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis.[Nat Commun. 2020]

• Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors.[Nature. 2012]
• Efficient temporally controlled targeted somatic mutagenesis in hepatocytes of the mouse.[Genesis. 2004]

• A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice.[Nat Protoc. 2008]

• Cultures with cryopreserved hepatocytes: applicability for studies of enzyme induction.[Chem Biol Interact. 2000]
• In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration.[Nature. 2013]

• Design and validation of a histological scoring system for nonalcoholic fatty liver disease.[Hepatology. 2005]

• imzML: Imaging Mass Spectrometry Markup Language: A common data format for mass spectrometry imaging.[Methods Mol Biol. 2011]
• MSiReader v1.0: Evolving Open-Source Mass Spectrometry Imaging Software for Targeted and Untargeted Analyses.[J Am Soc Mass Spectrom. 2018]

• Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand.[Cell. 2012]
• ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization.[Bioinformatics. 2015]

• In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration.[Nature. 2013]

• In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration.[Nature. 2013]

• Long-Term Expansion of Functional Mouse and Human Hepatocytes as 3D Organoids.[Cell. 2018]

• Lgr5⁺ stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool.[Development. 2019]
• The effect of ICRT-3 on Wnt signaling pathway in head and neck cancer.[J Cell Biochem. 2019]

• International network of cancer genome projects.[Nature. 2010]
• International Cancer Genome Consortium Data Portal--a one-stop shop for cancer genomics data.[Database (Oxford). 2011]

• Pan-cancer analysis of whole genomes.[Nature. 2020]

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kankerremmende eiwitten, UMC Utrecht, mutatie, RNF43 gen, anti-Wnt therapie

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• Antibiotica binnen een maand vooraf aan immuuntherapie met anti-PD medicijnen geeft veel slechtere resultaten op overall overleving dan zonder antibiotica bij verschillende vormen van primaire kanker.

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• Anti-PD medicijnen zoals nivolumab, Pembrolizumab en atezolizumab gegeven als immuuntherapie geven zeer goede resultaten bij verschillende vormen van kanker met solide tumoren, zelfs zonder Ligand-1 receptorstatus copy 1

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• Bacterien in uitzaaiingen van kankerpatienten zijn door Nederlandse onderzoekers in beeld gebracht en in een gedetailleerde catalogus opgeslagen

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• Behandelen van kanker verschuift steeds meer van chemotherapie naar biologische behandelingen, gerichte therapie waaronder immuuntherapie met gemoduleerde virussen die de minste bijwerkingen geven

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• Biomarkers zoals PD-L1, CD163+ en NRAS mutaties en gegevens zoals uitzaaiingen later ontstaan bepalen kans van effectiviteit van immuuntherapie met anti PD medicijnen bij melanomen

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• Bloedtest, uitgevoerd op in bloed circulerend DNA (ctDNA) op DNA mutaties afwijkingen, kan heel nauwkeurig nagenoeg alle vormen van kanker ontdekken.

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• CHRISPR-CAS9 infuus blijkt genezende behandeling voor erfelijke aandoening angio-oedeem, aldus tussenresultaten van internationale studie met Nederlandse deelname.

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• De biologische processen waarom en hoe kankercellen uitzaaien wordt beter begrepen, tumorcellen vroeger ontdekt en lijkt ook steeds beter te behandelen

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• De huidige staat van moleculair testen in het behandelen van kankerpatienten met solide tumoren. Een uitstekend overzichtsartikel met de nieuwste ontwikkelingen over RNA, DNA en eiwitten anno 2019

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• Diagnosetest PERCEPTION via AI - Kunstmatige Intelligentie ontwikkeld en met hulp van single-cell RNA-sequencing voorspelt nauwkeurig of een specifiek medicijn van de kankerpatient zal aanslaan of resistent zal zijn.

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• DRUP studie geeft bij 37 procent van de patienten alsnog een therapeutisch effect met 6 procent CR en 14 procent PR en 17 procent stabiele ziekte

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• EMA: Veel nieuwe kankermedicijnen in de EU hebben geen bewezen toegevoegde waarde blijkt uit Nederlandse studie naar goedgekeurde kankermedicijnen door het Europees Geneesmiddelenbureau (EMA).

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• ESMO - European Society for Medical Oncology heeft een gids uitgegeven voor patienten over hoe personalised medicine werkt en stand van zaken

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• FDA ondersteunt onderzoek naar personalised medicine op basis van mutaties ongeacht in welk lichaamsdeel de kanker zich het eerst openbaart.

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• Genetisch onderzoek via Germline testen (kiembaan testen) werd in periode 2013 tot 2019 in Georgie en Californie bij slechts 7 procent gedaan onder 1 369 602 patienten met twee jaar kanker.

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• Geneesmiddel (ARS1620) verandert kankergen (KRAS mutatie) dat kwaadaardige tumoren beschermt tegen immuunsysteem in een doelwit voor immuunsysteem en helpt immuuntherapie kankercellen te elimineren

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• Gentherapie zoals Chrispr-cas en base-editors zijn zeer succesvol bij erfelijke ziekten waaronder ook vormen van kanker zoals sikkelcelziekte

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• Gerichte behandelingen met Aurora kinaseremmers geven soms uitstekende resultaten bij veel vormen van kanker. Een reviewstudie

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• Immuuntherapie met HER2-gerichte CT-0508 (CAR-Macrofaag therapie) geeft bij solide tumoren van verschillende vormen van kanker met HER2 positieve expressie hoopvolle resultaten

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• Immuuntherapie met pembrolizumab bij patiënten met verschillende vormen van uitgezaaide kanker met hoge microsatellietinstabiliteit (MSI-H) en DNA-mismatch-reparatie-deficiënte (dMMR) geeft uitstekende en duurzame resultaten op overall overleving

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• Immuuntherapie met nivolumab zorgt voor duurzame en sterk verbeterde overall overleving bij verschillende vormen van kanker, melanomen, longkanker en nierkanker copy 1

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• Internationale groep van 180 wetenschappers stelt rapport op hoe en met welke niet-toxische middelen - voedingsstoffen de effectiviteit te verbeteren, recidieven te voorkomen en de bijwerkingen te verminderen van personalised medicine

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• Irina Kareva gebruikt wiskundige modellen die de dynamiek van kanker beschrijven, met het doel nieuwe geneesmiddelen te ontwikkelen die gericht zijn op tumoren.

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• Kanker-actueel kan en wil helpen - begeleiden bij aanvragen van een volledig biomoleculair receptorenonderzoek en genenonderzoek

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• Kankermedicijnen geven in de klinische praktijk veel minder effect dan uit de studies van farmaceutische bedrijven is aangetoond. Maar zijn wel ontzettend duur.

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• Kankerremmende eiwitten kunnen bij mutatie die gen uitschakelt veranderen van kankerremmend in stimulerend, ontdekten Nederlandse onderzoekers

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• Larotrectinib geeft bijzonder goede resultaten (76 procent respons met 12 procent complete remissies) bij alle vormen van solide tumoren met een positieve TRK Fusion mutatie

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• Larotrectinib: Met de goedkeuring van Larotrectinib op basis van 1 specifieke afwijking en niet op basis van primaire tumor zorgt de FDA voor een doorbraak in het behandelen van kanker

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• Lenvatinib Plus Pembrolizumab bij patiënten met inoperabele gevorderde nierkanker, buikvlieskanker, melanomen en andere gevorderde kanker met solide tumoren geeft uitstekende resultaten met meer dan de helft remissies van 50 procent of meer copy 1

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• Medicijnen voorschrijven op basis van DNA profiel van de patient voorkomt 30 procent minder bijwerkingen blijkt uit internationale studie onder leiding van LUMC Leiden

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• MSC-1 een medicijn dat de groei van de kankerstamcellen afremt door LIF blokkade en immuunsysteem activeert laat spectaculair goede resultaten zien in fase I studie.

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• Mytomorrows breidt aanbod aan experimentele medicijnen voor kankerpatienten uit met 11 nieuwe nog niet geregistreerde medicijnen en stelt deze beschikbaar voor uitbehandelde kankerpatienten

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• Nederland betaalt veel meer voor kankermedicijnen, soms tot 50 procent of meer, dan andere landen blijkt uit vergelijkend onderzoek tussen 18 landen copy 1

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• NCI-MATCH-studie toont aan dat een biomoleculaire analyse - DNA en receptorenonderzoek - belangrijk is in hoe een kankerpatient te behandelen.

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• Nieuw medicijn - PD-0332991 - stopt groei hersentumoren Glioblastoom in dierproeven. Zodra gestopt werd met dit medicijn gingen de tumoren weer groeien. Fase I studie bij 33 patienten met nierkanker en lymfklierkanker bevestigt veiligheid van dit middel

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• Nieuwe, dure kankermedicijnen zijn voortaan sneller beschikbaar door het Drug Access Protocol (DAP) dat is ontwikkeld door oncologen, verzekeraars en Zorginstituut Nederland

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• Overzicht van alle wereldwijd geregistreerde medicijnen binnen immuuntherapie en lopende studies met immuuntherapie copy 1

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• Overzicht van studies met medicijnen en behandelingen om tumoren met KRAS mutaties aan te pakken. Vooral combinatiebehandelingen zijn veelbelovend.

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• PI3K/AKT/mTOR pathway speelt cruciale rol in apoptose proces, DNA herstel, metabolisme in de cel en angiogenese.

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• Pembrolizumab - Keytruda geeft bij solide tumoren van verschillende oorsprong 21 procent complete remissies en 53 procent gedeeltelijke remissies.

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• Personalised medicine door receptorenonderzoek geeft veel betere resultaten in fase 1 studies dan experimenteel onderzoek zonder receptorenonderzoek

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• Prof. Bernards over de doorbraak bij darmkanker met Kras mutatie en bij melanomen met BRAF mutatie in DWDD van donderdag 27 maart 2014

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• POLE mutatie: veel kankerpatienten met erfelijke vormen van kanker hebben naast een P1-ligand een POLE mutatie en reageren goed op immuuntherapie met anti-PD medicijnen - checkpointremmers als pembrolizumab en nivolumab

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• Radiotherapeutisch stimulerend middel NBTXR3 geeft in combinatie met anti-PD-1 medicijnen alsnog uitstekende resultaten bij patiënten die ziekteprogressie lieten zien ongeacht eerdere behandeling met anti-PD-1 medicijnen

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• Rozlytrek (entrectinib), een tyrosine kinase remmer, goedgekeurd door FDA als medicijn voor solide tumoren met NTRK (neurotrophic tyrosine receptor kinase) gene fusion. Dit is 3e goedgekeurde medicijn op basis van mutatie.

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• Tweede primaire vorm van kanker bij een kankerpatient wordt steeds vaker bekend bij de diagnose (2 tot 17 procent) door betere diagnose technieken en verfijnder biomoleculair onderzoek

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• Tumorindeling mede aan de hand van biomarkers - biomoleculaire profielen is nodig en zal behandelingen sterk veranderen voor veel kankerpatiënten. Van 10 procent nu tot 50 procent straks. Aldus grote studie van het TOGA

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• Vaccin tegen KRAS positief gemuteerde vormen van kanker - darmkankers en longkanker o.a. - wordt gecombineerd met trametinib een anti-PD medicijn in fase I studie na hoopvolle resultaten.

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• Voorbeeldrapporten van receptoren en DNA testen - biomoleculaire profielen uitgevoerd door Caris Lifesciences - van alvleesklierkanker, hersentumoren, melanomen en longkanker

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• Vroege diagnose van kanker is de toekomst en is vaak al mogelijk: zie TED talk

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• Ziekte van Parkinson: prasinezumab, een monoklonaal antilichaam dat alfa-synucleïne bindt, vertraagt sterk de progressie van de ziekte van Parkinson in vergelijking met patienten die beste zorg kregen

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• Algemeen: overzicht van artikelen waarin personal medicine een rol speelt.