- Open Access
NHERF1/EBP50 and NF2 as diagnostic markers for choroid plexus tumors
© The Author(s). 2016
- Received: 11 April 2016
- Accepted: 21 May 2016
- Published: 27 May 2016
The adaptor protein NHERF1 (Na/H exchanger-3 regulatory factor-1) and its associated ezrin-radixin-moesin-merlin/neurofibromin-2 (ERM-NF2) family proteins are required for epithelial morphogenesis and have been implicated in cancer progression. NHERF1 is expressed in ependymal cells and constitutes a highly sensitive diagnostic marker for ependymoma, where it labels membrane polarity structures. Since NHERF1 and ERM-NF2 proteins show polarized expression in choroid plexus (CP) cells, we tested their diagnostic utility in CP neoplasms. NHERF1 immunohistochemistry in 43 adult and pediatric tumors with papillary morphology revealed strong apical plasma membrane staining in CP papilloma (WHO grade I) and cytoplasmic expression in CP carcinoma (WHO grade III). Ezrin and moesin showed similar but less distinctive staining. NHERF1 also labeled papillary tumors of the pineal region in a microlumen and focal apical membrane pattern, suggestive of a transitional morphology between CP papilloma and ependymoma. CP tumors of all grades could be differentiated from metastatic carcinomas with papillary architecture by NF2, which showed polarized membranous staining in CP tumors. NHERF1 and NF2 immunohistochemistry showed enhanced sensitivity and specificity for CP tumors compared to commonly used markers, including cytokeratins and Kir7.1, emerging as reliable diagnostic tools for the differential diagnosis of papillary tumors of the central nervous system.
- Choroid plexus tumors
- Papillary tumor of the pineal region
- CNS metastases
Choroid plexus (CP) cells are specialized polarized neuroepithelial cells that secrete the cerebrospinal fluid (CSF) and line the intraventricular papillae forming the CP . These cuboidal cells have domed apical plasma membrane rich in microvilli, basement membrane at the basal pole, and are connected laterally by tight junctions. Similarly to epithelial cells of other origins, CP cells express cytokeratins. Due to active secretory function, over 65 % of the nearly 400 solute carrier transporters are expressed by the CP epithelial cells. NHERF1/EBP50 (Na+/H+ exchanger 3 regulating factor 1; ezrin-radixin-moesin (ERM) binding phosphoprotein 50) is an adaptor protein that interacts with solute carriers, such as Na+/H+ exchanger 3, and many other signaling molecules through its amino (N)-terminal PDZ (PSD95-Dlg1-ZO1) domains [2, 3]. It also interacts thourgh its carboxyl (C)-terminal ERM-binding region with the four members of the ERM-NF2 family of cytoskeletal proteins: ezrin, radixin, moesin and merlin . The latter is the product of the neurofibromin 2 (NF2) gene, and will be called NF2 throughout. NHERF1 and ERM members form complexes at the plasma membrane required for epithelial morphogenesis and apical plasma membrane organization [5, 6]. Moreover, NHERF1 knockout mice have structural defects in various specialized membranes bearing microvilli or cilia that lead to functional deficits [7–11].
Beyond their morphogenetic rolce, both NHERF1 and ERM-NF2 family members are implicated in tumorigenesis. Mutations of the tumor suppressor NF2 cause a nervous system cancer predisposition syndrome, neurofibromatosis type 2 [2, 12, 13]. A tumor suppressor role has also been proposed for NHERF1, when localized at the membrane, through effects of the membrane-localized adaptor on its PTEN and β-catenin ligands [14–16]. Importantly, NHERF1 loss or displacement from the plasma membrane has been reported in aggressive tumors, including carcinomas and glioblastoma [14, 17, 18].
Due to their structural function and role in tumorigenesis, we analyzed the expression of NHERF1 and ERM-NF2 in normal CP and CP tumors. CP tumors arise most often in the pediatric population and, according to the 2007 World Health Organization (WHO) classification of central nervous system (CNS) tumors, they fall into three categories, in increasing order of aggressiveness: CP papilloma (WHO grade I), atypical CP papilloma (WHO grade II), where an increased mitotic index of 2 mitoses/10 high-power fields is a suggested diagnostic criterium, and CP carcinoma (WHO grade III) characterized by the presence of compact growth, necrosis, increased cellular density, nuclear pleomorphism, and more than 5 mitoses/10 high-power fields. Interestingly, we found that the distribution of NHERF1 changed with progression through the CP transformation spectrum: NHERF1 shifted from the apical plasma membrane in papilloma to the cytoplasm in carcinoma. This shift is not only compatible with a previously demonstrated tumor suppressor role for membrane-localized NHERF1, but can be used as diagnostic marker for distinguishing papillomas from carcinomas. Although rare in adults, the CP tumors do occur in this population and can pose a differential diagnostic dilemma with metastatic disease. We found that the distribution of NF2 can distinguish between CP tumors and papillary metastases, and we endorse using a combination of NHERF1 and NF2 immunohistochemistry (IHC) to address the differential diagnosis for papillary tumors of the CNS.
Formalin-fixed paraffin-embedded brain tumor resection specimens were obtained from the Departments of Pathology of the University of Texas Southwestern Medical Center, Dallas, TX, Vanderbilt University, Nashville, TN, St. Jude Children’s Research Hospital, Memphis, TN, and the Ohio State University, Columbus, OH. Fresh normal CP from autopsy was obtained from the Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX. These studies were performed in compliance with the ethical guidelines of the Helsinki Declaration and approved by the ethical committees for research on human subjects of the institutions above mentioned.
Histology, IHC and imaging
The specimens were processed for H& E staining and IHC as described , with antibodies for NHERF1 1:3200 (Thermo/Fisher, Waltham, MA), moesin 1:100 (3150, Cell Signaling Technology, Danvers, MA), Kir7.1 1:200, NF2 C-terminal 1:800 (C18) (see also ) (Santa Cruz Biotechnology, Santa Cruz, CA) and ezrin 1:400 (30252, BD Biosciences, San Jose, CA). Two certified neuropathologists reviewed independently the IHC results. Images were acquired and analyzed at various magnifications with an Aperio Scanscope CS2 whole slide image system (Leica Biosystems, San Diego, CA).
Freshly harvested CP was snap frozen, minced and Dounce-homogenized in ice-cold TNN lysis buffer [50 mM Tris HCl (pH 7.4)/150 mM NaCl/5 mM EDTA/0.5 % Nonidet P-40] containing proteinase inhibitor cocktail (Roche, Basel, Switzerland). After centrifugation, the protein concentration of the supernantant was measured and lysates with equal protein amounts were processed for Western Blot (WB) as described . Antibodies used were: radixin (C15, Santa Cruz Biotechnology), actin (Chemicon/Millipore, Billerica, MA) and NHERF1, ezrin and moesin, as mentioned above for IHC. LN229 glioblastoma cell lysates expressing small hairpin (sh) RNA for ezrin, radixin and moesin were prepared as described .
NHERF1 and NF2 have distinctive expression patterns in CP tumors
NHERF1 and NF2 in the differential diagnosis of papillary tumors of the CNS
No. cases Gender
Median age (range, yrs)
13 (6 F, 5 M)
Basolateral and apical PM
9 (4 M, 5 F)
Basolateral and apical PM
2 (1 M, 1 F)
40 (35, 46)
Basolateral and apical PM
4 (2 M; 2 F)
Cyt, apical PM
Basolateral and apical PM
1 (1 F)
Cyt or absent
Basolateral and apical PM
3 (2 M, 1 F)
1.7 (1, 2)
Cyt or absent
Basolateral and apical PM
5 (3 M, 2 F)
Microlumens, apical PM
6 (4 F, 2 M)
Absent, apical PM, nuclear
Analysis of the NHERF1/ERM-NF2 IHC profile in CP papilloma (WHO grade I) showed similarities but also differences with normal CP (Fig. 2b and Additional File 1: Figure S1). NHERF1 was strongly expressed in CP papilloma, almost exclusively at the apical plasma membrane. The cytoplasmic levels were either very low or undetectable. A notable exception were the areas of oncocytic-like change in which NHERF1 and, as discussed below, NF2 staining was identical to that of normal CP (Additional File 1: Figure S2), suggesting perhaps an intermediate hyperplastic lesion. The oncocytic-like change was focal and present only in few cases of CP papilloma, except for one case in which it formed the bulk of a cystic tumor. The subcellular localization of moesin, ezrin and NF2 in CP papilloma was similar to that from normal CP (Fig. 2a–b and Additional File 1: Figure S1). The continuous apical plasma membrane staining of NHERF1 was reliably detected in all 22 cases of CP papilloma and showed more robust staining than that of the inward rectifier potassium channel Kir7.1 (Fig. 2b).
The analysis of 4 cases of CP carcinoma (WHO grade III) showed cytoplasmic expression of NHERF1 in three of four cases and loss of apical plasma membrane staining in all cases (Fig. 2c–d and Additional File 1: Figure S3). Importantly, compact areas with similar morphology from CP papilloma and carcinoma could be readily distinguished by NHERF1 IHC (Additional File 1: Figure S3). NF2 showed focal areas of basolateral plasma membrane staining in CP carcinoma (Fig. 2c and Additional File 1: Figure S3) that, as discussed below, is important in demonstrating the CP origin of the tumor.
Resection specimens containing both normal CP and CP papilloma provided an opportunity to compare protein expression between non-neoplastic and neoplastic regions (Additional File 1: Figure S1). These were sometimes present on the same papillary trunk, showing continuity between the two forms (Additional File 1: Figure S4). We noted relatively decreased apical plasma membrane staining of NHERF1 and moesin in papilloma (Additional File 1: Figure S1). This suggests an attenuation of the density of microvilli at the apical plasma membrane in papilloma, without loss of cell polarity. The further loss of NHERF1 from the apical plasma membrane in carcinoma with either detectable or undetectable cytoplasmic expression (Fig. 2d) is compatible with loss of cell polarity, disorganized compact growth, and a more advanced stage of transformation. Although NF2 basolateral plasma membrane staining was preserved in normal CP and CP tumors, a decreased expression and a more focal distribution was observed with increasing tumor grade (Fig. 2c and Additional File 1: Figure S1). This tendency is most likely due to the known tumor suppressor function of NF2 [4, 13].
These results show that NHERF1 and NF2 staining patterns change along the CP normal to neoplastic progression spectrum. In particular, NHERF1 subcellular localization is very useful in differentiating CP papilloma with compact areas from tumors of higher grades.
NHERF1 is a diagnostic marker for papillary tumors of the pineal region (PTPR)
NF2 expression distinguishes CP tumors from metastatic papillary carcinomas
CP tumors are rare papillary neoplasms that present mostly in children, in approximately 80 % of cases. In contrast to CP papilloma for which total surgical resection is curative in the large majority of cases, CP carcinoma has an aggressive course requiring adjuvant therapy. The distinction between CP papilloma and carcinoma can be difficult, as areas of confluent growth and mitoses may be focal. In addition, routine IHC profiles do not differ significantly among the three grades of CP tumors. In particular, Kir7.1 has been shown to be a specific marker of CP papilloma . However, its sensitivity is approximately 67 % , and its staining is not as robust as for NHERF1. We show here that NHERF1 IHC may aid distinguishing between CP papilloma and CP carcinoma. Loss of NHERF1 apical plasma membrane staining or enhanced cytoplasmic expression points to areas of compact growth and mitoses and marks a more aggressive phenotype with loss of membrane polarity. The cut off is not as clear in atypical CP papilloma, but an NHERF1 staining pattern similar to CP carcinoma or ependymoma favors a more aggressive phenotype and tumor recurrences. In the latter scenario, the differential diagnosis with ependymoma, especially the papillary variant, needs to be entertained, and a small biopsy containing only compact areas may be difficult to interpret.
NHERF1 IHC also shows a characteristic pattern in PTPR, with mixed microlumen and focal apical plasma membrane staining, and distinguishes this tumor from CP papilloma. It is also consistent with PTPR being intermediate in differentiation between ependymomas and CP tumors as previously suggested . A recent study has shown that PTPR has a distinct molecular profile from ependymoma and CP papilloma . Although many IHC markers have been studied, including EMA, cytokeratins, GFAP, MAP-2, and Kir7.1 [29, 30], none show a diagnostically useful, reliable staining profile. The location of the tumor, papillary architecture, and presence of microlumens by NHERF1 IHC offer the best clues to the diagnosis of this entity. Testing for NHERF1 IHC of a large series of other CNS neoplasms that could arise in any location, including the pineal gland, did not detect microlumens in 22 cases of WHO grade II and III diffuse gliomas, 4 cases of pilocytic astrocytomas and 2 cases of atypical teratoid/rhabdoid tumors .
While metastatic disease to the CNS usually affects an older population than CP tumors and the history of a primary tumor may be known, diagnostic uncertainties between papillary metastasis and CP tumors do occur. We have found that NF2 is a marker for CP with a characteristic subcellular localization at the basolateral plasma membrane in normal or transformed CP. This subcellular localization was not detected in metastatic papillary carcinomas and may thus be used to differentiate between CP tumors and metastatic carcinomas. Moreover, whereas all 32 choroid plexus tumors in this series expressed NF2, three out of six papillary metastatic tumors were negative for NF2. Loss of chromosome 22 locus for NF2 is a frequent event in papillary thyroid carcinoma , explaining that two such tumors lacked NF2. NF2 mutations, albeit rare, were reported in lung adenocarcinoma, as well .
Similar progressive NHERF1 changes as in CP tumors, with loss of apical plasma membrane expression and cytoplasmic accumulation have been noted previously in the colorectal cancer transformation sequence . It is tempting to propose that a normal - > papilloma - > carcinoma transformation sequence takes place for CP tumors as well. Due to the rarity of CP tumors, only few documented cases of CP tumor histologic progression are reported in the literature [33, 34]. An additional case of worsening histological disease is the aCPP2 case in our study. Intriguingly, a high proportion of these progressive cases fall into the adult rather than the pediatric population. Recent molecular profiling studies segregated CP carcinomas from CP papillomas, and adult from pediatric disease [21–23]. However, these studies did not address the possibility of progressive disease. Additional investigations are required to delineate the full spectrum of CP tumors, and delineate prognostic markers aiming patient stratification for clinical management.
NHERF1 and NF2 IHC is diagnostically useful for papillary tumors of the CNS. NHERF1 emerges as a marker of CP tumors based on its structural role in specialized epithelia. NHERF1 has been shown to exert a tumor suppressor function when localized at the plasma membrane [14, 18], and perhaps loss of plasma membrane localization permits oncogenic progression in CP tumors. Moreover, an oncogenic function of NHERF1 in the cytoplasm has been proposed in both colorectal and melanoma cells [14, 35]. As therapeutic efforts are underway to inhibit the association of NHERF1 to its PDZ-domain ligands [36, 37], its role needs to be further investigated in this lethal childhood malignancy.
C, carboxyl; CNS, central nervous system; CP, choroid plexus; CSF, cerebrospinal fluid; ERM, ezrin-radixin-moesin; IHC, immunohistochemistry; N, amino; NF2, neurofibromin 2; NHERF1/EBP50, Na/H exchanger regulatory factor 1/ ERM-binding phosphoprotein 50; PDZ, PSD95-Dlg1-ZO1; PTPR, papillary tumor of the pineal region; WB, Western blot; WHO, World Health Organization.
This paper is dedicated to the Japanese molecular biologist Katsuko Tani who had important contributions in deciphering the secretory pathways of the cell. Those who were privileged to know her were impressed by her strong devotion to mentoring and collegiality. She was a stimulating teacher and role model for her students, and an affectionate and supportive friend for her colleagues. Katsuko was a person of great dignity and generosity. Through her own example of scientific dedication and rigorous analysis, she has been a constant source of encouragement for maintaining high standards in scientific research for all of us. The authors also thank Chang Fong for imaging help, and Niccole Williams and Agatha Villegas for administrative assistance.
Part of this study was funded by National Institutes of Health grant CA107201 to MMG.
Availability of data and materials
For data and materials, please contact MMG at email@example.com.
MMG performed conception and design of the study, development of methodology, acquisition of data, analysis and interpretation of data, writing and review of the manuscript, study supervision and provided part of the material support. BCM, NLL and CFT performed acquisition of data and review of the manuscript. PS and XZ performed development of methodology and acquisition of data. BAO, TON, VR and KJH performed acquisition of data. JMR performed acquisition of data, analysis and interpretation of data, review of the manuscript, and provided administrative and part of the material support. All authors read and approved the final manuscript.
The authors declare no competing interests.
Ethics approval and consent to participate
These studies were performed in compliance with the ethical guidelines of the Helsinki Declaration and approved by the ethical committees for research on human subjects of the University of Texas Southwestern Medical Center, Dallas, TX, Vanderbilt University, Nashville, TN, St. Jude Children’s Research Hospital, Memphis, TN, and the Ohio State University, Columbus, OH.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Liddelow SA. Development of the choroid plexus and blood-CSF barrier. Front Neurosci. 2015;9:32.View ArticlePubMedPubMed CentralGoogle Scholar
- Georgescu MM, Morales FC, Molina JR, Hayashi Y. Roles of NHERF1/EBP50 in cancer. Curr Mol Med. 2008;8:459–68.View ArticlePubMedGoogle Scholar
- Weinman EJ, Wang Y, Wang F, Greer C, Steplock D, Shenolikar S. A C-terminal PDZ motif in NHE3 binds NHERF-1 and enhances cAMP inhibition of sodium-hydrogen exchange. Biochemistry. 2003;42:12662–8.View ArticlePubMedGoogle Scholar
- Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol. 2002;3:586–99.View ArticlePubMedGoogle Scholar
- Georgescu MM, Cote G, Agarwal NK, White 3rd CL. NHERF1/EBP50 controls morphogenesis of 3D colonic glands by stabilizing PTEN and ezrin-radixin-moesin proteins at the apical membrane. Neoplasia. 2014;16:365–74.View ArticlePubMedPubMed CentralGoogle Scholar
- Viswanatha R, Bretscher A, Garbett D. Dynamics of ezrin and EBP50 in regulating microvilli on the apical aspect of epithelial cells. Biochem Soc Trans. 2014;42:189–94.View ArticlePubMedPubMed CentralGoogle Scholar
- Broere N, Chen M, Cinar A, Singh AK, Hillesheim J, Riederer B, Lunnemann M, Rottinghaus I, Krabbenhoft A, Engelhardt R, Rausch B, Weinman EJ, Donowitz M, Hubbard A, Kocher O, de Jonge HR, Hogema BM, Seidler U. Defective jejunal and colonic salt absorption and alteredNa (+)/H (+) exchanger 3 (NHE3) activity in NHE regulatory factor 1 (NHERF1) adaptor protein-deficient mice. Pflugers Archiv - Eur J Physiol. 2009;457:1079–91.View ArticleGoogle Scholar
- Georgescu MM, Yell P, Mobley BC, Shang P, Georgescu T, Wang SH, Canoll P, Hatanpaa KJ, White CL 3rd, Raisanen JM. NHERF1/EBP50 is an organizer of polarity structures and a diagnostic marker in ependymoma. Acta Neuropathol Commun. 2015;3:11.View ArticlePubMedPubMed CentralGoogle Scholar
- Kamiya K, Michel V, Giraudet F, Riederer B, Foucher I, Papal S, Perfettini I, Le Gal S, Verpy E, Xia W, Seidler U, Georgescu MM, Avan P, El-Amraoui A, Petit C. An unusually powerful mode of low-frequency sound interference due to defective hair bundles of the auditory outer hair cells. Proc Natl Acad Sci U S A. 2014;111:9307–12.View ArticlePubMedPubMed CentralGoogle Scholar
- Morales FC, Takahashi Y, Kreimann EL, Georgescu MM. Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia. Proc Natl Acad Sci U S A. 2004;101:17705–10.View ArticlePubMedPubMed CentralGoogle Scholar
- Treat AC, Wheeler DS, Stolz DB, Tsang M, Friedman PA, Romero G. The PDZ Protein Na+/H+ Exchanger Regulatory Factor-1 (NHERF1) Regulates Planar Cell Polarity and Motile Cilia Organization. PLoS One. 2016;11:e0153144.View ArticlePubMedPubMed CentralGoogle Scholar
- Clucas J, Valderrama F. ERM proteins in cancer progression. J Cell Sci. 2014;127:267–75.View ArticlePubMedGoogle Scholar
- Petrilli AM, Fernandez-Valle C. Role of Merlin/NF2 inactivation in tumor biology. Oncogene. 2015;35:537–48.View ArticlePubMedPubMed CentralGoogle Scholar
- Hayashi Y, Molina JR, Hamilton SR, Georgescu MM. NHERF1/EBP50 is a new marker in colorectal cancer. Neoplasia. 2010;12:1013–22.View ArticlePubMedPubMed CentralGoogle Scholar
- Kreimann EL, Morales FC, de Orbeta-Cruz J, Takahashi Y, Adams H, Liu TJ, McCrea PD, Georgescu MM. Cortical stabilization of beta-catenin contributes to NHERF1/EBP50 tumor suppressor function. Oncogene. 2007;26:5290–9.View ArticlePubMedGoogle Scholar
- Takahashi Y, Morales FC, Kreimann EL, Georgescu MM. PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling. EMBO J. 2006;25:910–20.View ArticlePubMedPubMed CentralGoogle Scholar
- Mangia A, Chiriatti A, Bellizzi A, Malfettone A, Stea B, Zito FA, Reshkin SJ, Simone G, Paradiso A. Biological role of NHERF1 protein expression in breast cancer. Histopathology. 2009;55:600–8.View ArticlePubMedGoogle Scholar
- Molina JR, Morales FC, Hayashi Y, Aldape KD, Georgescu MM. Loss of PTEN binding adapter protein NHERF1 from plasma membrane in glioblastoma contributes to PTEN inactivation. Cancer Res. 2010;70:6697–703.View ArticlePubMedPubMed CentralGoogle Scholar
- Morales FC, Molina JR, Hayashi Y, Georgescu MM. Overexpresssion of ezrin inactivates NF2 tumor suppressor in glioblastoma. Neuro Oncol. 2010;12:528–39.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhu X, Morales FC, Agarwal NK, Dogruluk T, Gagea M, Georgescu MM. Moesin is a glioma progression marker that induces proliferation and Wnt/beta-catenin pathway activation via interaction with CD44. Cancer Res. 2013;73:1142–55.View ArticlePubMedGoogle Scholar
- Thomas C, Sill M, Ruland V, Witten A, Hartung S, Kordes U, Jeibmann A, Beschorner R, Keyvani K, Bergmann M, Mittelbronn M, Pietsch T, Felsberg J, Monoranu CM, Varlet P, Hauser P, Olar A, Grundy RG, Wolff JE, Korshunov A, Jones DT, Bewerunge-Hudler M, Hovestadt V, von Deimling A, Pfister SM, Paulus W, Capper D, Hasselblatt M. Methylation profiling of choroid plexus tumors reveals 3 clinically distinct subgroups. Neuro Oncol. 2016;18:790–6.View ArticlePubMedGoogle Scholar
- Japp AS, Gessi M, Messing-Junger M, Denkhaus D, Zur Muhlen A, Wolff JE, Hartung S, Kordes U, Klein-Hitpass L, Pietsch T. High-resolution genomic analysis does not qualify atypical plexus papilloma as a separate entity among choroid plexus tumors. J Neuropathol Exp Neurol. 2015;74:110–20.View ArticlePubMedGoogle Scholar
- Merino DM, Shlien A, Villani A, Pienkowska M, Mack S, Ramaswamy V, Shih D, Tatevossian R, Novokmet A, Choufani S, Dvir R, Ben-Arush M, Harris BT, Hwang EI, Lulla R, Pfister SM, Achatz MI, Jabado N, Finlay JL, Weksberg R, Bouffet E, Hawkins C, Taylor MD, Tabori U, Ellison DW, Gilbertson RJ, Malkin D. Molecular characterization of choroid plexus tumors reveals novel clinically relevant subgroups. Clin Cancer Res. 2015;21:184–92.View ArticlePubMedGoogle Scholar
- Jouvet A, Fauchon F, Liberski P, Saint-Pierre G, Didier-Bazes M, Heitzmann A, Delisle MB, Biassette HA, Vincent S, Mikol J, Streichenberger N, Ahboucha S, Brisson C, Belin MF, Fevre-Montange M. Papillary tumor of the pineal region. Am J Surg Pathol. 2003;27:505–12.View ArticlePubMedGoogle Scholar
- Fevre Montange M, Vasiljevic A, Champier J, Jouvet A. Papillary tumor of the pineal region: Histopathological characterization and review of the literature. Neurochirurgie. 2015;61:138–42.View ArticlePubMedGoogle Scholar
- Hasselblatt M, Bohm C, Tatenhorst L, Dinh V, Newrzella D, Keyvani K, Jeibmann A, Buerger H, Rickert CH, Paulus W. Identification of novel diagnostic markers for choroid plexus tumors: a microarray-based approach. Am J Surg Pathol. 2006;30:66–74.View ArticlePubMedGoogle Scholar
- Lehman NL. Central nervous system tumors with ependymal features: a broadened spectrum of primarily ependymal differentiation? J Neuropathol Exp Neurol. 2008;67:177–88.View ArticlePubMedGoogle Scholar
- Heim S, Sill M, Jones DT, Vasiljevic A, Jouvet A, Fevre-Montange M, Wesseling P, Beschorner R, Mittelbronn M, Kohlhof P, Hovestadt V, Johann P, Kool M, Pajtler KW, Korshunov A, Ruland V, Sperveslage J, Thomas C, Witt H, von Deimling A, Paulus W, Pfister SM, Capper D, Hasselblatt M. Papillary Tumor of the Pineal Region: A Distinct Molecular Entity. Brain Pathol. 2015;26:199–205.View ArticlePubMedGoogle Scholar
- Fevre Montange M, Vasiljevic A, Bergemer Fouquet AM, Bernier M, Champier J, Chretien F, Figarella-Branger D, Kemeny JL, Lechapt-Zalcman E, Michalak S, Miquel C, Mokthari K, Pommepuy I, Quintin Roue I, Rousseau A, Saint-Pierre G, Salon C, Uro-Coste E, Varlet P, Kratzer I, Ghersi-Egea JF, Jouvet A. Histopathologic and ultrastructural features and claudin expression in papillary tumors of the pineal region: a multicenter analysis. Am J Surg Pathol. 2012;36:916–28.View ArticlePubMedGoogle Scholar
- Hasselblatt M, Blumcke I, Jeibmann A, Rickert CH, Jouvet A, van de Nes JA, Kuchelmeister K, Brunn A, Fevre-Montange M, Paulus W. Immunohistochemical profile and chromosomal imbalances in papillary tumours of the pineal region. Neuropathol Appl Neurobiol. 2006;32:278–83.View ArticlePubMedGoogle Scholar
- Cancer Genome Atlas Research N. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–90.View ArticleGoogle Scholar
- Pirazzoli V, Nebhan C, Song X, Wurtz A, Walther Z, Cai G, Zhao Z, Jia P, de Stanchina E, Shapiro EM, Gale M, Yin R, Horn L, Carbone DP, Stephens PJ, Miller V, Gettinger S, Pao W, Politi K. Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1. Cell Rep. 2014;7:999–1008.View ArticlePubMedPubMed CentralGoogle Scholar
- Dhillon RS, Wang YY, McKelvie PA, O’Brien B. Progression of choroid plexus papilloma. J Clin Neurosci. 2013;20:1775–8.View ArticlePubMedGoogle Scholar
- Jeibmann A, Wrede B, Peters O, Wolff JE, Paulus W, Hasselblatt M. Malignant progression in choroid plexus papillomas. J Neurosurg. 2007;107:199–202.PubMedGoogle Scholar
- Fang XY, Song R, Chen W, Yang YY, Gu YH, Shu YQ, Wu XD, Wu XF, Sun Y, Shen Y, Xu Q. PRL-3 Promotes the Malignant Progression of Melanoma via Triggering Dephosphorylation and Cytoplasmic Localization of NHERF1. J Invest Dermatol. 2015;135:2273–82.View ArticlePubMedGoogle Scholar
- Fitzpatrick JM, Pellegrini M, Cushing PR, Mierke DF. Small molecule inhibition of the Na(+)/H(+) exchange regulatory factor 1 and parathyroid hormone 1 receptor interaction. Biochemistry. 2014;53:5916–22.View ArticlePubMedPubMed CentralGoogle Scholar
- Mayasundari A, Ferreira AM, He L, Mahindroo N, Bashford D, Fujii N. Rational design of the first small-molecule antagonists of NHERF1/EBP50 PDZ domains. Bioorg Med Chem Lett. 2008;18:942–5.View ArticlePubMedGoogle Scholar