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 2020

Sebastian M Waszak, Giles W Robinson, Brian L Gudenas, Kyle S Smith, Antoine Forget, Marija Kojic, Jesus Garcia-Lopez, Jennifer Hadley, Kayla V Hamilton, Emilie Indersie, Ivo Buchhalter, Jules Kerssemakers, Natalie Jäger, Tanvi Sharma, Tobias Rausch, Marcel Kool, Dominik Sturm, David T W Jones, Aksana Vasilyeva, Ruth G Tatevossian, Geoffrey Neale, Bérangère Lombard, Damarys Loew, Joy Nakitandwe, Michael Rusch, Daniel C Bowers, Anne Bendel, Sonia Partap, Murali Chintagumpala, John Crawford, Nicholas G Gottardo, Amy Smith, Christelle Dufour, Stefan Rutkowski, Tone Eggen, Finn Wesenberg, Kristina Kjaerheim, Maria Feychting, Birgitta Lannering, Joachim Schüz, Christoffer Johansen, Tina V Andersen, Martin Röösli, Claudia E Kuehni, Michael Grotzer, Marc Remke, Stéphanie Puget, Kristian W Pajtler, Till Milde, Olaf Witt, Marina Ryzhova, Andrey Korshunov, Brent A Orr, David W Ellison, Laurence Brugieres, Peter Lichter, Kim E Nichols, Amar Gajjar, Brandon J Wainwright, Olivier Ayrault, Jan O Korbel, Paul A Northcott, Stefan M Pfister (2020 Apr 17)

Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Nature : 396-401 : DOI : 10.1038/s41586-020-2164-5

Year of publication 2019

Francesca Bufalieri, Paola Infante, Flavia Bernardi, Miriam Caimano, Paolo Romania, Marta Moretti, Ludovica Lospinoso Severini, Julie Talbot, Ombretta Melaiu, Mirella Tanori, Laura Di Magno, Diana Bellavia, Carlo Capalbo, Stéphanie Puget, Enrico De Smaele, Gianluca Canettieri, Daniele Guardavaccaro, Luca Busino, Angelo Peschiaroli, Simonetta Pazzaglia, Giuseppe Giannini, Gerry Melino, Franco Locatelli, Alberto Gulino, Olivier Ayrault, Doriana Fruci, Lucia Di Marcotullio (2019 Jul 26)

ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP.

Nature communications : 3304 : DOI : 10.1038/s41467-019-11093-0
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

Year of publication 2018

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

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
Malika Foy, Océane Anézo, Simon Saule, Nathalie Planque (2017 Mar 13)

PRL-3/PTP4A3 phosphatase regulates integrin β1 in adhesion structures during migration of human ocular melanoma cells.

Experimental cell research : DOI : S0014-4827(17)30117-9
All publications