Signaling in development and brain tumors

Olivier Ayrault

Olivier Ayrault Team Leader Tel:

Organ-specific mechanisms governing organ development and tumor formation are closely linked. During cerebellar development, several signaling pathways play key roles in cell fate determination, axis formation, and patterning. However, deregulation in those developmental processes contribute to medulloblastoma (MB), the most common malignant pediatric brain tumor. To date, one third of patients die from MB and existing therapies for MB have severe side effects, which make finding new drugs a priority. MB is divided into four subgroups in which distinct pathways are affected. Group 1 is associated with mutations in the WNT pathway (15% of cases), whereas group 2 shows a constitutive activation of Sonic Hedgehog (SHH) signaling (25% of cases). Group 3 and 4 are less characterized.

Our general team goal is to decipher fundamental mechanisms related to the complex biology of MB. Because signaling pathways that are dysregulated in brain cancer are also at the basis of normal cerebellar development, we perform our studies back and forth in the normal development and cancer contexts. To elucidate mechanisms involved in MB, we are using adapted and innovative tools in the area of biochemistry, cell biology and mouse models (Fig. 1).

Figure 1: Schéma représentant les stratégies et les techniques utilisées pour l’étude du médulloblastome.
Figure 1: Overview of strategies/techniques involved in medulloblastoma studies.

Recently, we and others uncovered that the bHLH transcription factor Atoh1 plays a crucial role in SHH MB. Because Atoh1 acts as a “lineage addiction transcription factor” in SHH MBs and its down regulation inhibits tumor progression, deciphering molecular pathways that regulate Atoh1 might help to identify potential new targets for therapeutic interventions. However, how Atoh1 is regulated at the protein level had remained poorly understood.

In this context, our recent finding shows that SHH regulates Atoh1 stability by preventing its phosphodependent degradation by the E3 ubiquitin ligase Huwe1 (Forget*, Bihannic*, et al., Dev. Cell, 2014). Strikingly, we found that lower HUWE1 expression level defined a subset of patients with poor prognosis within the SHH subgroup in which Atoh1 is upregulated. Hence, the crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a collaborative network that could be further targeted in SHH MB (Fig. 2).

In conclusion, we anticipate that further characterization of Atoh1 regulation and function will provide novel insights into Atoh1 as a potential therapeutic target in the treatment of SHH MB.

Figure 2: Interaction entre Atoh1 en Huwe1 au cours du développement normal et du MB SHH. (Forget*. Bihannic*. et al. Dev. Cell, 2014).
Figure 2: Schematic representation of developmental pathway disruption between cerebellar development and cancer. (Forget*, Bihannic* et al., 2014, Dev. Cell)

Key publications

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

Year of publication 2017

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

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
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
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

Year of publication 2015

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
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