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Inactivating Mutations of RNF43 Confer Wnt Dependency in Pancreatic Ductal Adenocarcinoma

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Inactivating Mutations of RNF43 Confer Wnt Dependency in Pancreatic Ductal Adenocarcinoma Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma Xiaomo Jianga,1, Huai-Xiang Haoa,1, Joseph D. Growneyb, Steve Woolfendenb, Cindy Bottigliob, Nicholas Ngc,BoLua, Mindy H. Hsiehc, Linda Bagdasarianb, Ronald Meyerb, Timothy R. Smithc, Monika Avelloa, Olga Charlata, Yang Xiea, Jeffery A. Portera, Shifeng Panc, Jun Liuc, Margaret E. McLaughlinb, and Feng Conga,2 aDevelopmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, MA 02139; bOncology Translational Medicine, Novartis Pharma, Cambridge, MA 02139; and cGenomics Institute of Novartis Research Foundation, San Diego, CA 92121 Edited by Jeremy Nathans, Johns Hopkins University, Baltimore, MD, and approved May 31, 2013 (received for review April 16, 2013) A growing number of agents targeting ligand-induced Wnt/β-cat- including LRP6 antibody (9, 10), Frizzled antibody (11), and Por- enin signaling are being developed for cancer therapy. However, cupine inhibitor (12), are being developed. However, it is chal- clinical development of these molecules is challenging because of lenging to develop therapeutic agents without a defined patient the lack of a genetic strategy to identify human tumors dependent population, and we do not have enough knowledge about human on ligand-induced Wnt/β-catenin signaling. Ubiquitin E3 ligase tumors dependent on ligand-induced Wnt/β-catenin signaling. ring finger 43 (RNF43) has been suggested as a negative regulator We have shown that transmembrane E3 ubiqutin ligase ZNRF3 of Wnt signaling, and mutations of RNF43 have been identified in negatively regulates Wnt/β-catenin signaling through promoting various tumors, including cystic pancreatic tumors. However, loss the degradation of Frizzled, and the activity of ZNRF3 is inhibited of function study of RNF43 in cell culture has not been conducted, by R-spondin proteins (13). Ring finger 43 (RNF43) is struc- and the functional significance of RNF43 mutations in cancer is turally related to ZNRF3. Intestinal-specific deletion of both unknown. Here, we show that RNF43 inhibits Wnt/β-catenin sig- Znrf3 and Rnf43 induces hyperproliferation of intestinal crypts naling by reducing the membrane level of Frizzled in pancreatic and formation of intestinal adenoma in mice (14). These studies cancer cells, serving as a negative feedback mechanism. Inhibition suggest that RNF43 serves as a negative regulator of Wnt/β-cat- of endogenous Wnt/β-catenin signaling increased the cell surface enin signaling similar to ZNRF3. However, a cellular system in level of Frizzled. A panel of 39 pancreatic cancer cell lines was which RNF43 plays a critical role has not been identified, and, tested for Wnt dependency using LGK974, a selective Porcupine therefore, in vitro loss-of-function studies of RNF43 have not inhibitor being examined in a phase 1 clinical trial. Strikingly, all been possible. RNF43 is frequently mutated in intraductal pap- LGK974-sensitive lines carried inactivating mutations of RNF43. In- illary mucinous neoplasm (IPMN) and mucinous cystic neo- hibition of Wnt secretion, depletion of β-catenin, or expression of plasm (MCN) of the pancreas (15,16). IPMN and MCN are wild-type RNF43 blocked proliferation of RNF43 mutant but not potential precursors to pancreatic ductal adenocarcinoma RNF43–wild-type pancreatic cancer cells. LGK974 inhibited prolif- (PDAC), which is extremely aggressive and associated with eration and induced differentiation of RNF43-mutant pancreatic a dismal prognosis and few proven therapeutic options (17–20). adenocarcinoma xenograft models. Our data suggest that muta- Here, we studied the function of RNF43 in human pancreatic tional inactivation of RNF43 in pancreatic adenocarcinoma confers adenocarcinoma cells. We found that RNF43 suppressed Wnt Wnt dependency, and the presence of RNF43 mutations could be signaling by decreasing membrane levels of Frizzled in pancre- used as a predictive biomarker for patient selection supporting the atic cancer, functioning as a negative feedback mechanism. By clinical development of Wnt inhibitors in subtypes of cancer. testing Wnt dependency in a large panel of pancreatic cancer cell lines, we discovered that all cell lines whose proliferation was he evolutionarily conserved Wnt/β-catenin signaling pathway strongly inhibited by a Porcupine inhibitor had homozygous Tplays critical roles in embryonic development and adult tissue RNF43 loss-of-function mutations. Growth of RNF43-mutant homeostasis (1, 2). Wnt signaling regulates the turnover of the lines was blocked upon depletion of β-catenin or RNF43 re- transcription cofactor β-catenin and controls key developmental expression. Treatment of RNF43-mutant tumors in vivo with gene expression programs (3). In the absence of Wnt pathway a Porcupine inhibitor resulted in growth inhibition and differ- RNF43 activation, cytosolic β-catenin is degraded by the β-catenin destruc- entiation. Therefore, we propose that mutation can serve tion complex, consisting of adeomatous polyposis coli (APC), as a predictive biomarker for identifying Wnt ligand-dependent AXIN1/2, and glycogen synthase kinase 3α/β (GSK3α/β). Wnt li- pancreatic cancers that may be responsive to upstream Wnt gand activates its two receptors, Frizzled and LRP5/6, and inac- pathway inhibitors. tivates the β-catenin destruction complex. Stabilized β-catenin CELL BIOLOGY Results enters the nucleus, binds to the TCF family of transcription fac- Negative Regulation of Wnt Signaling by RNF43 in Pancreatic Cancer tors, and activates transcription. Secretion of Wnt proteins re- RNF43 quires Porcupine (PORCN), a membrane bound O-acyltransferase Cells. Because is frequently mutated in cystic pancreatic dedicated to Wnt posttranslational acylation (4, 5). Precise regu- tumors (15, 16), we hypothesized that RNF43 is an essential lation of Wnt signaling is critical and various feedback control mechanisms exist to ensure proper signaling output. Aberrant activation of Wnt/β-catenin signaling has been im- Author contributions: X.J., H.-X.H., J.D.G., T.R.S., J.A.P., S.P., J.L., M.E.M., and F.C. designed research; X.J., H.-X.H., J.D.G., S.W., C.B., N.N., B.L., M.H.H., L.B., R.M., M.A., O.C., Y.X., and plicated in tumorigenesis, and many downstream components of F.C. performed research; H.-X.H., J.D.G., S.W., C.B., N.N., B.L., M.H.H., L.B., R.M., M.A., O.C., the Wnt pathway are mutated in cancers (6). Truncation muta- Y.X., J.L., M.E.M., and F.C. analyzed data; and X.J., H.-X.H., M.E.M., and F.C. wrote tions of APC are found in 80% of colorectal cancer. Stabilization the paper. mutations of CTNNB1 (β-catenin) and loss of function mutations The authors declare no conflict of interest. of AXIN1/2 are also found in cancers. Despite intense research, This article is a PNAS Direct Submission. targeting Wnt/β-catenin signaling in cancers harboring down- 1X.J. and H.-X.H. contributed equally to this work. stream pathway mutations remains challenging because of the 2To whom correspondence should be addressed. E-mail: [email protected]. lack of tractable targets (7, 8). However, there are several potential This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. targets upstream in the Wnt signaling pathway, and various agents, 1073/pnas.1307218110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1307218110 PNAS | July 30, 2013 | vol. 110 | no. 31 | 12649–12654 Downloaded by guest on October 3, 2021 regulator of Wnt/β-catenin signaling in pancreatic cancer. RNF43 RNF43 (RNF43 siR) in YAPC cells. As seen in Fig. 1E, expression loss-of-function experiments were performed in YAPC, a pan- of siRNA-resistant RNF43 largely abolished the effect of RNF43 creatic adenocarcinoma cell line. Depletion of RNF43 using siRNA on Frizzled levels, suggesting the activity of RNF43 siRNA two independent siRNAs (Fig. S1A)significantly increased is on target. Depletion of RNF43 also increased the expression SuperTopflash (STF) Wnt reporter activity, either in the absence of AXIN2,aβ-catenin target gene, and this effect is abolished by or presence of Wnt3a conditioned medium (Fig. 1A). LGK974 the expression of RNF43 siR (Fig. 1F). On the basis of the is a Porcupine inhibitor that specifically inhibits Wnt secretion threshold cycle (Ct) values observed in a quantitative RT-PCR and is under clinical evaluation (www.clinicaltrials.gov/ct2/show/ assay, RNF43 is dominantly expressed compared with ZNRF3 NCT01351103?term=lgk974&rank=1). RNF43 siRNA-induced in YAPC cells (Fig. S1B). Consistent with the idea that RNF43 STF activity in the absence of exogenous Wnt3a is inhibited by targets Wnt receptors for degradation, RNF43 can be coimmu- Porcupine inhibitor LGK974 and IWP-2 (12) (Fig. 1B), indicating noprecipitated with Frizzled and LRP6 (Fig. S2). Together, these that this activity depends on the expression of endogenous Wnt results suggest that RNF43 negatively regulates Wnt/β-catenin proteins. These results suggest that RNF43 actively suppresses signaling by decreasing membrane expression of Frizzled. autocrine Wnt/β-catenin signaling in YAPC cells. We next performed biochemical assays to characterize the Wnt/β-Catenin Signaling Suppresses the Membrane Expression of function of RNF43 in YAPC cells. Depletion of RNF43 in- Frizzled. Wnt/β-catenin signaling is under exquisite control, with creased the level of cytosolic β-catenin (Fig. 1C), in agreement multiple negative feedback control mechanisms to ensure the with increased STF reporter activity (Fig. 1A). Dishevelled proper signaling output. We and others have shown that ZNRF3 (DVL) is an intracellular signaling protein downstream of Friz- and RNF43 are β-catenin target genes (13, 14). Although such zled, and its phosphorylation is stimulated by Frizzled activation. data suggest that ZNRF3 and RNF43 might suppress membrane Depletion of RNF43 increased phosphorylation of DVL2 (Fig. Frizzled as a negative feedback loop, the effect of endogenous β 1C), suggesting that the activity of Frizzled is increased. Indeed, Wnt/ -catenin signaling on Frizzled expression has never been β depletion of RNF43 markedly increased the cell surface level of examined.
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