Signaling in development and brain tumors

Team Publications

Year of publication 2019

Maud Blanluet, Julien Masliah-Planchon, Irina Giurgea, Franck Bielle, Elodie Girard, Mamy Andrianteranagna, Stéphane Clemenceau, Christine Bourneix, Lydie Burglen, Diane Doummar, Audrey Rapinat, Badreddine Mohand Oumoussa, Olivier Ayrault, Celio Pouponnot, David Gentien, Gaëlle Pierron, Olivier Delattre, François Doz, Franck Bourdeaut (2019 Mar 9)

SHH medulloblastoma in a young adult with a TCF4 germline pathogenic variation.

Acta neuropathologica : DOI : 10.1007/s00401-019-01983-4 Learn more
Summary

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Chia-Hsiang Chang, Marco Zanini, Hamasseh Shirvani, Jia-Shing Cheng, Hua Yu, Chih-Hsin Feng, Audrey L Mercier, Shiue-Yu Hung, Antoine Forget, Chun-Hung Wang, Sara Maria Cigna, I-Ling Lu, Wei-Yi Chen, Sophie Leboucher, Won-Jing Wang, Martial Ruat, Nathalie Spassky, Jin-Wu Tsai, Olivier Ayrault (2019 Jan 30)

Atoh1 Controls Primary Cilia Formation to Allow for SHH-Triggered Granule Neuron Progenitor Proliferation.

Developmental cell : 184-199.e5 : DOI : S1534-5807(18)31085-2 Learn more
Summary

During cerebellar development, granule neuron progenitors (GNPs) proliferate by transducing Sonic Hedgehog (SHH) signaling via the primary cilium. Precise regulation of ciliogenesis, thus, ensures proper GNP pool expansion. Here, we report that Atoh1, a transcription factor required for GNPs formation, controls the presence of primary cilia, maintaining GNPs responsiveness to SHH. Loss of primary cilia abolishes the ability of Atoh1 to keep GNPs in a proliferative state. Mechanistically, Atoh1 promotes ciliogenesis by transcriptionally regulating Cep131, which facilitates centriolar satellite (CS) clustering to the basal body. Importantly, ectopic expression of Cep131 counteracts the effects of Atoh1 loss in GNPs by restoring proper localization of CS and ciliogenesis. This Atoh1-CS-primary cilium-SHH pro-proliferative pathway is also conserved in SHH-type medulloblastoma, a pediatric brain tumor arising from the GNPs. Together, our data reveal how Atoh1 modulates the primary cilium to regulate GNPs development.

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Year of publication 2018

Forget Antoine, Martignetti Loredana, Puget Stéphanie, Calzone Laurence, Brabetz Sebastian, Picard Daniel, Montagud Arnau, Liva Stéphane, Sta Alexandre, Dingli Florent, Arras Guillaume, Rivera Jaime, Loew Damarys, Besnard Aurore, Lacombe Joëlle, Pagès Mélanie, Varlet Pascale, Dufour Christelle, Yu Hua, L. Mercier Audrey, Indersie Emilie, Chivet Anaïs, Leboucher Sophie, Sieber Laura, Beccaria Kevin, Gombert Michael, D. Meyer Frauke, Qin Nan, Bartl Jasmin, Chavez Lukas, Okonechnikov Konstantin, Sharma Tanvi, Thatikonda Venu, Bourdeaut Franck, Pouponnot Celio, Ramaswamy Vijay, Korshunov Andrey, Borkhardt Arndt, Reifenberger Guido, Poullet Patrick, D. Taylor Michael, Kool Marcel, M. Pfister Stefan, Kawauchi Daisuke, Barillot Emmanuel, Remke Marc, Ayrault Olivier (2018 Sep 10)

Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling

Cancer Cell : 34 : 379-395 : DOI : 10.1016/j.ccell.2018.08.002 Learn more
Summary

The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.

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Alexandra Garancher, Charles Y Lin, Morgane Morabito, Wilfrid Richer, Nathalie Rocques, Magalie Larcher, Laure Bihannic, Kyle Smith, Catherine Miquel, Sophie Leboucher, Nirmitha I Herath, Fanny Dupuy, Pascale Varlet, Christine Haberler, Christine Walczak, Nadine El Tayara, Andreas Volk, Stéphanie Puget, François Doz, Olivier Delattre, Sabine Druillennec, Olivier Ayrault, Robert J Wechsler-Reya, Alain Eychène, Franck Bourdeaut, Paul A Northcott, Celio Pouponnot (2018 Mar 14)

NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma.

Cancer cell : 435-449.e6 : DOI : 10.1016/j.ccell.2018.02.006 Learn more
Summary

Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.

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Year of publication 2017

Katie B Grausam, Samuel D R Dooyema, Laure Bihannic, Hasitha Premathilake, A Sorana Morrissy, Antoine Forget, Amanda M Schaefer, Justin H Gundelach, Slobodan Macura, Diane M Maher, Xin Wang, Alex H Heglin, Xijin Ge, Erliang Zeng, Stephanie Puget, Indra Chandrasekar, Kameswaran Surendran, Richard J Bram, Ulrich Schüller, Michael D Talyor, Olivier Ayrault, Haotian Zhao (2017 May 12)

ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas.

Cancer research : 3766-3777 : DOI : 10.1158/0008-5472.CAN-16-1836 Learn more
Summary

Medulloblastoma arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we used mouse medulloblastoma models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive medulloblastoma subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed tomice, which develop SHH-driven medulloblastoma, animals withtransgene expression developed highly penetrant medulloblastoma at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH medulloblastoma. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely,expression was detected consistently in recurrent and metastatic SHH medulloblastoma. Chromatin immunoprecipitation sequencing and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying medulloblastoma metastasis that offers possible therapeutic opportunities..

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Neuerburg A, Friesen O, Zuckermann M, Rajendran V, Gronych J, Ayrault O, Korshunov A, Jones DT, Kool M,Northcott PA, Lichter P, Cortés-Ledesma F, Pfister SM, Liu HK (2017 Mar 20)

Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme.

Nature Communications : 8 : 14758 : DOI : 10.1038/ncomms14758 Learn more
Summary

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Year of publication 2016

Noelia Urbán, Debbie L C van den Berg, Antoine Forget, Jimena Andersen, Jeroen A A Demmers, Charles Hunt, Olivier Ayrault, François Guillemot (2016 Jul 16)

Return to quiescence of mouse neural stem cells by degradation of a proactivation protein.

Science (New York, N.Y.) : 292-5 : DOI : 10.1126/science.aaf4802 Learn more
Summary

Quiescence is essential for long-term maintenance of adult stem cells. Niche signals regulate the transit of stem cells from dormant to activated states. Here, we show that the E3-ubiquitin ligase Huwe1 (HECT, UBA, and WWE domain-containing 1) is required for proliferating stem cells of the adult mouse hippocampus to return to quiescence. Huwe1 destabilizes proactivation protein Ascl1 (achaete-scute family bHLH transcription factor 1) in proliferating hippocampal stem cells, which prevents accumulation of cyclin Ds and promotes the return to a resting state. When stem cells fail to return to quiescence, the proliferative stem cell pool becomes depleted. Thus, long-term maintenance of hippocampal neurogenesis depends on the return of stem cells to a transient quiescent state through the rapid degradation of a key proactivation factor.

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Zhi-Yan Han, Wilfrid Richer, Paul Fréneaux, Céline Chauvin, Carlo Lucchesi, Delphine Guillemot, Camille Grison, Delphine Lequin, Gaelle Pierron, Julien Masliah-Planchon, André Nicolas, Dominique Ranchère-Vince, Pascale Varlet, Stéphanie Puget, Isabelle Janoueix-Lerosey, Olivier Ayrault, Didier Surdez, Olivier Delattre, Franck Bourdeaut (2016 Jan 29)

The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation.

Nature communications : 10421 : DOI : 10.1038/ncomms10421 Learn more
Summary

Rhabdoid tumours (RTs) are highly aggressive tumours of infancy, frequently localized in the central nervous system (CNS) where they are termed atypical teratoid/rhabdoid tumours (AT/RTs) and characterized by bi-allelic inactivation of the SMARCB1 tumour suppressor gene. In this study, by temporal control of tamoxifen injection in Smarcb1(flox/flox);Rosa26-Cre(ERT2) mice, we explore the phenotypes associated with Smarcb1 inactivation at different developmental stages. Injection before E6, at birth or at 2 months of age recapitulates previously described phenotypes including embryonic lethality, hepatic toxicity or development of T-cell lymphomas, respectively. Injection between E6 and E10 leads to high penetrance tumours, mainly intra-cranial, with short delays (median: 3 months). These tumours demonstrate anatomical, morphological and gene expression profiles consistent with those of human AT/RTs. Moreover, intra- and inter-species comparisons of tumours reveal that human and mouse RTs can be split into different entities that may underline the variety of RT cells of origin.

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A Sorana Morrissy, Livia Garzia, David J H Shih, Scott Zuyderduyn, Xi Huang, Patryk Skowron, Marc Remke, Florence M G Cavalli, Vijay Ramaswamy, Patricia E Lindsay, Salomeh Jelveh, Laura K Donovan, Xin Wang, Betty Luu, Kory Zayne, Yisu Li, Chelsea Mayoh, Nina Thiessen, Eloi Mercier, Karen L Mungall, Yusanne Ma, Kane Tse, Thomas Zeng, Karey Shumansky, Andrew J L Roth, Sohrab Shah, Hamza Farooq, Noriyuki Kijima, Borja L Holgado, John J Y Lee, Stuart Matan-Lithwick, Jessica Liu, Stephen C Mack, Alex Manno, K A Michealraj, Carolina Nor, John Peacock, Lei Qin, Juri Reimand, Adi Rolider, Yuan Y Thompson, Xiaochong Wu, Trevor Pugh, Adrian Ally, Mikhail Bilenky, Yaron S N Butterfield, Rebecca Carlsen, Young Cheng, Eric Chuah, Richard D Corbett, Noreen Dhalla, An He, Darlene Lee, Haiyan I Li, William Long, Michael Mayo, Patrick Plettner, Jenny Q Qian, Jacqueline E Schein, Angela Tam, Tina Wong, Inanc Birol, Yongjun Zhao, Claudia C Faria, José Pimentel, Sofia Nunes, Tarek Shalaby, Michael Grotzer, Ian F Pollack, Ronald L Hamilton, Xiao-Nan Li, Anne E Bendel, Daniel W Fults, Andrew W Walter, Toshihiro Kumabe, Teiji Tominaga, V Peter Collins, Yoon-Jae Cho, Caitlin Hoffman, David Lyden, Jeffrey H Wisoff, James H Garvin, Duncan S Stearns, Luca Massimi, Ulrich Schüller, Jaroslav Sterba, Karel Zitterbart, Stephanie Puget, Olivier Ayrault, Sandra E Dunn, Daniela P C Tirapelli, Carlos G Carlotti, Helen Wheeler, Andrew R Hallahan, Wendy Ingram, Tobey J MacDonald, Jeffrey J Olson, Erwin G Van Meir, Ji-Yeoun Lee, Kyu-Chang Wang, Seung-Ki Kim, Byung-Kyu Cho, Torsten Pietsch, Gudrun Fleischhack, Stephan Tippelt, Young Shin Ra, Simon Bailey, Janet C Lindsey, Steven C Clifford, Charles G Eberhart, Michael K Cooper, Roger J Packer, Maura Massimino, Maria Luisa Garre, Ute Bartels, Uri Tabori, Cynthia E Hawkins, Peter Dirks, Eric Bouffet, James T Rutka, Robert J Wechsler-Reya, William A Weiss, Lara S Collier, Adam J Dupuy, Andrey Korshunov, David T W Jones, Marcel Kool, Paul A Northcott, Stefan M Pfister, David A Largaespada, Andrew J Mungall, Richard A Moore, Nada Jabado, Gary D Bader, Steven J M Jones, David Malkin, Marco A Marra, Michael D Taylor (2016 Jan 14)

Divergent clonal selection dominates medulloblastoma at recurrence.

Nature : 351-7 : DOI : 10.1038/nature16478 Learn more
Summary

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

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Year of publication 2015

Laure Bihannic, Olivier Ayrault (2015 Dec 22)

Insights into cerebellar development and medulloblastoma.

Bulletin du cancer : 30-40 : DOI : 10.1016/j.bulcan.2015.11.002 Learn more
Summary

Cerebellar development is an extensive process that begins during early embryonic stages and persists more than one year after birth in human. Therefore, the cerebellum is susceptible to acquire various developmental abnormalities leading to numerous diseases such as medulloblastoma, the most common pediatric malignant brain tumor. One third of the patients with medulloblastoma are incurable and survivors have a poor quality of life due to the aggressiveness of the broad-spectrum treatments. Within the past few years, it has been highlighted that medulloblastoma is a heterogeneous disease that is divided in four molecular subgroups. This recent advance in the field, combined with the development of associated preclinical models for each subgroup, should enable, in the future, the discovery and use of targeted therapy in clinical treatments for each subtype of medulloblastoma. In this review, we first aim to show how deregulation of cerebellar development can lead to medulloblastoma formation and then to present the advances in the molecular subgrouping of medulloblastoma and the associated preclinical models.

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Lisa Ivanschitz, Yuki Takahashi, Florence Jollivet, Olivier Ayrault, Morgane Le Bras, Hugues de Thé (2015 Nov 19)

PML IV/ARF interaction enhances p53 SUMO-1 conjugation, activation, and senescence.

Proceedings of the National Academy of Sciences of the United States of America : 14278-83 : DOI : 10.1073/pnas.1507540112 Learn more
Summary

Promyelocytic leukemia protein (PML) nuclear bodies (NBs) recruit multiple partners, including p53 and many of its regulators. NBs are believed to facilitate several posttranslational modifications and are key regulators of senescence. PML, the organizer of NBs, is expressed as a number of splice variants that all efficiently recruit p53 partners. However, overexpression of only one of them, PML IV, triggers p53-driven senescence. Here, we show that PML IV specifically binds ARF, a key p53 regulator. Similar to ARF, PML IV enhances global SUMO-1 conjugation, particularly that of p53, resulting in p53 stabilization and activation. ARF interacts with and stabilizes the NB-associated UBC9 SUMO-conjugating enzyme, possibly explaining PML IV-enhanced SUMOylation. These results unexpectedly link two key tumor suppressors, highlighting their convergence for global control of SUMO conjugation, p53 activation, and senescence induction.

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Lucile Hoch, Helene Faure, Hermine Roudaut, Angele Schoenfelder, Andre Mann, Nicolas Girard, Laure Bihannic, Olivier Ayrault, Elena Petricci, Maurizio Taddei, Didier Rognan, Martial Ruat (2015 Feb 1)

MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptor.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology : 1817-29 : DOI : 10.1096/fj.14-267849 Learn more
Summary

The Smoothened (Smo) receptor, a member of class F G protein-coupled receptors, is the main transducer of the Hedgehog (Hh) signaling pathway implicated in a wide range of developmental and adult processes. Smo is the target of anticancer drugs that bind to a long and narrow cavity in the 7-transmembrane (7TM) domain. X-ray structures of human Smo (hSmo) bound to several ligands have revealed 2 types of 7TM-directed antagonists: those binding mostly to extracellular loops (site 1, e.g., LY2940680) and those penetrating deeply in the 7TM cavity (site 2, e.g., SANT-1). Here we report the development of the acylguanidine MRT-92, which displays subnanomolar antagonist activity against Smo in various Hh cell-based assays. MRT-92 inhibits rodent cerebellar granule cell proliferation induced by Hh pathway activation through pharmacologic (half maximal inhibitory concentration [IC50] = 0.4 nM) or genetic manipulation. Using [(3)H]MRT-92 (Kd = 0.3 nM for hSmo), we created a comprehensive framework for the interaction of small molecule modulators with hSmo and for understanding chemoresistance linked to hSmo mutations. Guided by molecular docking and site-directed mutagenesis data, our work convincingly confirms that MRT-92 simultaneously recognized and occupied both sites 1 and 2. Our data demonstrate the existence of a third type of Smo antagonists, those entirely filling the Smo binding cavity from the upper extracellular part to the lower cytoplasmic-proximal subpocket. Our studies should help design novel potent Smo antagonists and more effective therapeutic strategies for treating Hh-linked cancers and associated chemoresistance.

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Year of publication 2013

Antoine Forget, Laure Bihannic, Sara Maria Cigna, Coralie Lefevre, Marc Remke, Monia Barnat, Sophie Dodier, Hamasseh Shirvani, Audrey Mercier, Aurore Mensah, Mickael Garcia, Sandrine Humbert, Michael D Taylor, Anna Lasorella, Olivier Ayrault (2013 Oct 22)

Shh signaling protects Atoh1 from degradation mediated by the E3 ubiquitin ligase Huwe1 in neural precursors.

Developmental cell : 649-61 : DOI : 10.1016/j.devcel.2014.05.014 Learn more
Summary

Signaling networks controlled by Sonic hedgehog (SHH) and the transcription factor Atoh1 regulate the proliferation and differentiation of cerebellar granule neuron progenitors (GNPs). Deregulations in those developmental processes lead to medulloblastoma formation, the most common malignant brain tumor in childhood. Although the protein Atoh1 is a key factor during both cerebellar development and medulloblastoma formation, up-to-date detailed mechanisms underlying its function and regulation have remained poorly understood. Here, we report that SHH regulates Atoh1 stability by preventing its phosphodependent degradation by the E3 ubiquitin ligase Huwe1. Our results reveal that SHH and Atoh1 contribute to a positive autoregulatory loop promoting neuronal precursor expansion. Consequently, Huwe1 loss in mouse SHH medulloblastoma illustrates the disruption of this developmental mechanism in cancer. Hence, the crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a collaborative network that could be further targeted in medulloblastoma.

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Year of publication 2010

Olivier Ayrault, Haotian Zhao, Frederique Zindy, Chunxu Qu, Charles J Sherr, Martine F Roussel (2010 Jun 1)

Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells.

Cancer research : 5618-27 : DOI : 10.1158/0008-5472.CAN-09-3740 Learn more
Summary

The morphogen and mitogen Sonic Hedgehog (Shh) activates a Gli1-dependent transcription program that drives proliferation of granule neuron progenitors (GNP) within the external germinal layer of the postnatally developing cerebellum. Medulloblastomas with mutations activating the Shh signaling pathway preferentially arise within the external germinal layer, and the tumor cells closely resemble GNPs. Atoh1/Math1, a basic helix-loop-helix transcription factor essential for GNP histogenesis, does not induce medulloblastomas when expressed in primary mouse GNPs that are explanted from the early postnatal cerebellum and transplanted back into the brains of naïve mice. However, enforced expression of Atoh1 in primary GNPs enhances the oncogenicity of cells overexpressing Gli1 by almost three orders of magnitude. Unlike Gli1, Atoh1 cannot support GNP proliferation in the absence of Shh signaling and does not govern expression of canonical cell cycle genes. Instead, Atoh1 maintains GNPs in a Shh-responsive state by regulating genes that trigger neuronal differentiation, including many expressed in response to bone morphogenic protein-4. Therefore, by targeting multiple genes regulating the differentiation state of GNPs, Atoh1 collaborates with the pro-proliferative Gli1-dependent transcriptional program to influence medulloblastoma development.

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Year of publication 2009

Olivier Ayrault, Michael D Godeny, Christopher Dillon, Frederique Zindy, Patrick Fitzgerald, Martine F Roussel, Helen M Beere (2009 Sep 23)

Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma.

Proceedings of the National Academy of Sciences of the United States of America : 17037-42 : DOI : 10.1073/pnas.0902880106 Learn more
Summary

Elevated expression of HSP90 is observed in many tumor types and is associated with a limited clinical response. Targeting HSP90 using inhibitors such as 17-DMAG (17-desmethoxy-17-N,N-dimethylaminoethylaminogeldanamycin) has shown limited therapeutic success. HSP90 regulates the function of several proteins implicated in tumorigenesis although the precise mechanism through which 17-DMAG regulates tumor cell survival remains unclear. We observed a requirement for p53 in mediating 17-DMAG-induced cell death. The sensitivity of primary mouse embryonic fibroblasts and tumor cells to 17-DMAG-induced apoptosis depended on the p53 status. Wild-type MEFs underwent 17-DMAG-induced caspase-dependent cell death, whilst those lacking p53 failed to do so. Interestingly p53-dependent cell death occurred independently of Atm or Arf. Primary tumor cells derived from two models of murine medulloblastoma (Ptch1(+/-);Ink4c(-/-) and p53(FL/FL);Nestin-Cre(+); Ink4c(-/-)) that retain and lack p53 function, respectively, displayed a dependence on functional p53 to engage 17-DMAG-induced apoptosis. Strikingly, 17-DMAG treatment in an allograft model of Ptch1(+/-);Ink4c(-/-) but not p53(FL/FL);Nestin-Cre(+); Ink4c(-/-) tumor cells prevented tumor growth in vivo. Our data suggest that p53 status is a likely predictor of the sensitivity of tumors to 17-DMAG.

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