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The Endosomal Protein CEMIP Links WNT Signaling to MEK1–ERK1/2

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The Endosomal Protein CEMIP Links WNT Signaling to MEK1–ERK1/2 Published OnlineFirst June 18, 2018; DOI: 10.1158/0008-5472.CAN-17-3149 Cancer Molecular Cell Biology Research The Endosomal Protein CEMIP Links WNT Signaling to MEK1–ERK1/2 Activation in Selumetinib-Resistant Intestinal Organoids Hong Quan Duong1,2,3,4, Ivan Nemazanyy5, Florian Rambow6, Seng Chuan Tang1,2, Sylvain Delaunay1,7, Lars Tharun8, Alexandra Florin8, Reinhard Buttner€ 8, Daniel Vandaele9, Pierre Close1,7, Jean-Christophe Marine6, Kateryna Shostak1,2, and Alain Chariot1,2,10 Abstract MAPK signaling pathways are constitutively active in decrease of both ERK1/2 signaling and c-Myc. Together, our colon cancer and also promote acquired resistance to MEK1 data identify a cross-talk between Wnt and MAPK signaling inhibition. Here, we demonstrate that BRAFV600E-mutated cascades, which involves CEMIP. Activation of this pathway colorectal cancers acquire resistance to MEK1 inhibition by promotes survival by potentially regulating levels of specific inducing expression of the scaffold protein CEMIP through amino acids via a Myc-associated cascade. Targeting this a b-catenin– and FRA-1–dependent pathway. CEMIP was node may provide a promising avenue for treatment of found in endosomes and bound MEK1 to sustain ERK1/2 colon cancers that have acquired resistance to targeted activation in MEK1 inhibitor–resistant BRAFV600E-mutated therapies. colorectal cancers. The CEMIP-dependent pathway main- tained c-Myc protein levels through ERK1/2 and provided Significance: MEK1 inhibitor–resistant colorectal cancer metabolic advantage in resistant cells, potentially by sus- relies on the scaffold and endosomal protein CEMIP to main- taining amino acids synthesis. CEMIP silencing circum- tain ERK1/2 signaling and Myc-driven transcription. Cancer Res; vented resistance to MEK1 inhibition, partly, through a 78(16); 4533–48. Ó2018 AACR. Introduction underlying genetic alterations are loss-of-function mutations of the adenomatous polyposis coli (APC) gene, which leads to Colorectal cancer is the second leading cause of death from b-catenin activation and constitutive Wnt signaling, followed by cancer in Western countries and arises from a variety of genetic gain-of-function mutations in KRAS or BRAF proto-oncogenes alterations that result in the constitutive activation of both Wnt- (1). RAS signals though the RAF Ser/Thr kinase family and triggers and ErbB-dependent oncogenic signaling pathways. Among the the subsequent activation of the mitogen-activated protein/extra- cellular signal–regulated kinase 1 and 2 (MEK1/2) as well as the extracellular signal–regulated kinase 1 and 2 (ERK1/2). This 1Interdisciplinary Cluster for Applied Genoproteomics (GIGA), GIGA-Molecular signaling cascade gained significant attention due to the high Biology of Diseases, University of Liege, CHU, Sart-Tilman, Liege, Belgium. frequency of KRAS and BRAF mutations found in human cancers 2 Laboratory of Medical Chemistry, University of Liege, CHU, Sart-Tilman, Liège, (2, 3). Indeed, activating mutations of KRAS are found in 40% of Belgium. 3Institute of Research and Development, Duy Tan University, Quang 4 advanced colorectal cancer (4). In addition, the BRAF valine 600 Trung, Danang, Vietnam. Department of Cancer Research, Vinmec Research V600E Institute of Stem Cell and Gene Technology, Hanoi, Vietnam. 5Paris Descartes (BRAF ) mutation, which leads to constitutive activation of University, Sorbonne Paris Cite, Paris, France. 6Laboratory for Molecular Cancer BRAF, is found in approximately 11% of colorectal cancers and Biology, VIB Center for Cancer Biology and KULeuven Department of Oncology, confers poor prognosis (5–7). As the pharmacologic inhibition of Leuven, Belgium. 7Institute for Pathology, University Hospital Cologne, Cologne, KRAS remains challenging, alternative approaches targeting 8 Germany. Laboratory of Cancer Signaling, University of Liege, Liege, Belgium. downstream RAS effectors (RAF and MEK1) have been proposed 9 Gastroenterology Department, University of Liege, CHU, Sart-Tilman, Liege, but were poorly effective in monotherapy for the treatment of Belgium. 10Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wallonia, Belgium. colorectal cancer, largely because of a feedback reactivation of MAPK signaling (8, 9). This reactivation occurs through the Note: Supplementary data for this article are available at Cancer Research amplification of the driving oncogene KRAS or BRAF in colorectal Online (http://cancerres.aacrjournals.org/). cells treated with MEK1 inhibitors (10, 11). Other mechanisms K. Shostak and A. Chariot contributed equally to this article. involve the EGFR/HER1–dependent reactivation of MAPK in Corresponding Author: Alain Chariot, Laboratory of Medical Chemistry, GIGA BRAFV600E-mutated colorectal cancer cells treated with a BRAF Molecular Biology of Diseases, Tour GIGA, þ2 B34, Sart-Tilman, University of inhibitor (12, 13). Similarly, MAPK reactivation in KRAS-mutated Liege, Liege 4000, Belgium. Phone: 32-043662472; Fax: 32-043664534; colorectal cancer cells subjected to MEK1 inhibition also results E-mail: [email protected]. from the induction of HER3 (14). Clinical trials in which RAF and doi: 10.1158/0008-5472.CAN-17-3149 EGFR or RAF and MEK are cotargeted to suppress the feedback Ó2018 American Association for Cancer Research. reactivation of MAPK signaling were carried out but patients www.aacrjournals.org 4533 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst June 18, 2018; DOI: 10.1158/0008-5472.CAN-17-3149 Duong et al. showing initial benefit nevertheless developed resistance and (20 ng/mL), Noggin (100 ng/mL), and R-Spondin (500 ng/mL) recurrence in disease progression (15). Here again, resistant was added every 2 days. Apc-mutated organoids were cultured colorectal cancer cells had KRAS or BRAF amplification as well in DMEM/F12 supplemented with EGF (20 ng/mL), Noggin þ as an activating MEK1 mutation (16). (100 ng/mL) without R-Spondin. The enrichment of Lgr5 stem The RAS–RAF–MEK1–ERK1/2 cascade is critically reliant on cells in ex vivo organoids generated with intestinal crypts from scaffold proteins, which assemble pathway molecules to regulate C57BL/6 mice was carried out by treating them with a combina- signaling. Among them are Ras GTPase-activating-like protein tion of valproic acid (1 mmol/L) and CHIR999021 (3 mmol/L), a (IQGAP1) as well as kinase suppressor of RAS (KSR; refs. 17–20). GSK3 inhibitor. Another scaffold protein is KIAA1199, now referred to as CEMIP ("Cell Migration-inducing and hyaluronan-binding protein"), Generation of selumetinib-resistant colorectal cancer cell lines whose expression is enhanced in cervical, breast, and colorectal (HT-29/SR, COLO-205/SR, SW480/SR and HCT116/SR) and cancer (21–25). CEMIP promotes cell survival and invasion, at selumetinib-resistant ex vivo organoids least through EGFR-dependent MEK1 and ERK1/2 activation in Four colorectal cancer cell lines (HT-29, COLO-205, SW480, cervical and breast cancer cells (23). It remains unclear which and HCT116) were used as parental cell lines (HT-29/P, COLO- scaffold proteins, if any, are specifically involved in MAPK reac- 205/P, SW480/P, and HCT116/P), from which were generated the tivation in colorectal cells showing intrinsic or acquired resistance selumetinib-resistant cell lines (HT-29/SR, COLO-205/SR, to BRAF or MEK1 inhibitors. SW480/SR, and HCT116/SR). These cell lines were generated by It is intuitive that both Wnt- and MAPK-dependent signaling repeated subculturing cells in the presence of incrementally in- pathways are interconnected in promoting resistance to targeted creasing concentrations of selumetinib (from 0.05 to 1.5 mmol/L therapies. Here we define CEMIP as a MEK1-binding protein for HT-29/P and SW480/P cells; from 0.05 to 2 mmol/L for induced by Wnt signaling. CEMIP promotes the acquired resis- HCT116/P cells; from 0.005 to 0.3 mmol/L for COLO-205/P) for tance to MEK1 inhibition in BRAFV600E-mutated colorectal cancer 6 months. For the maintenance of selumetinib-resistant colorectal cells, at least through ERK1/2 signaling and Myc. This CEMIP- cancer cell lines, the maximum concentration of selumetinib, dependent cascade is essential for amino acid synthesis in resis- namely 1.5 mmol/L (HT-29/SR and SW480/SR cells), 2 mmol/L tant cells. Collectively, our data define CEMIP as a key driver of (HCT116/SR cells), and 0.3 mmol/L selumetinib (COLO-205/SR resistance to MEK1 inhibition in BRAFV600E-mutated colorectal cells) was added into the normal medium. cancer that acts upstream of ERK1/2 and Myc cascade. For the generation of selumetinib-resistant ex vivo organoids, þ organoids generated from Apc /Min mice were first cultured with Materials and Methods 1 mmol/L of selumetinib for two weeks. The concentration was then increased by 0.5 mmol/L every two weeks to reach a final Cell culture and reagents concentration of 5 mmol/L. Colorectal cancer cell lines (HT-29, HCT116, SW480 and COLO-205) were purchased from ATCC in 2009. These cells were Lentiviral cell infection characterized by ATCC, using a comprehensive database of short Control shRNA, CEMIP, Myc, TAK1 and FRA-1 shRNA lentiviral fi tandem repeat (STR) DNA pro les. Frozen aliquots of freshly pLKO1-puro plasmid constructs were purchased from Sigma. cultured cells were generated and experiments were done with Control shRNA and CEMIP shRNA lentiviral pLKO1-puro- resuscitated cells cultured for less than 6 months. All cell lines IPTG-inducible plasmid constructs were
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