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Research Papers:

Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma

Alex Cazes, Lucille Lopez-Delisle, Konstantina Tsarovina, Cécile Pierre-Eugène, Katleen De Preter, Michel Peuchmaur, André Nicolas, Claire Provost, Caroline Louis-Brennetot, Romain Daveau, Candy Kumps, Ilaria Cascone, Gudrun Schleiermacher, Aurélie Prignon, Frank Speleman, Hermann Rohrer, Olivier Delattre and Isabelle Janoueix-Lerosey _

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Oncotarget. 2014; 5:2688-2702. https://doi.org/10.18632/oncotarget.1883

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Abstract

Alex Cazes1,2, Lucille Lopez-Delisle1,2, Konstantina Tsarovina3, Cécile Pierre-Eugène1,2, Katleen De Preter4, Michel Peuchmaur5,6, André Nicolas7, Claire Provost8, Caroline Louis-Brennetot1,2, Romain Daveau1,2, Candy Kumps4, Ilaria Cascone9, Gudrun Schleiermacher1,2,10, Aurélie Prignon8, Frank Speleman4, Hermann Rohrer3, Olivier Delattre1,2 and Isabelle Janoueix-Lerosey1,2

1 Inserm U830, 26 rue d’Ulm, 75005 Paris, France.

2 Institut Curie, Centre de Recherche, 26 rue d’Ulm, 75005 Paris, France.

3 Research Group Developmental Neurobiology, Max Planck Institute for Brain Research, Max-von-Laue-Str. 4, 60438 Frankfurt/M, Germany.

4 Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.

5 Departement of Pathology, AP-HP, Hôpital Universitaire Robert Debré, 48 boulevard Sérurier, 75019 Paris, France.

6 Université Diderot Paris 7, Paris Sorbonne Cité, Paris, France.

7 Platform of Experimental Pathology, Institut Curie, 26 rue d’Ulm, 75005 Paris, France.

8 LIMP (Laboratoire d’Imagerie Moléculaire Positonique), Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France.

9 Laboratoire CRRET, EAC CNRS 7149, Université Paris 12-Val de Marne, 61, avenue du Général de Gaulle, 94010 Créteil, France.

10 Institut Curie, Département de Pédiatrie, 26 rue d’Ulm, 75005 Paris, France.

Correspondence:

Isabelle Janoueix-Lerosey, email:

Keywords: Neuroblastoma, ALK, neurogenesis, therapeutic target, RET

Received: March 24, 2014 Accepted: April 01, 2014 Published: April 02, 2014

Abstract

Activating mutations of the ALK (Anaplastic lymphoma Kinase) gene have been identified in sporadic and familial cases of neuroblastoma, a cancer of early childhood arising from the sympathetic nervous system (SNS). To decipher ALK function in neuroblastoma predisposition and oncogenesis, we have characterized knock-in (KI) mice bearing the two most frequent mutations observed in neuroblastoma patients. A dramatic enlargement of sympathetic ganglia is observed in AlkF1178L mice from embryonic to adult stages associated with an increased proliferation of sympathetic neuroblasts from E14.5 to birth. In a MYCN transgenic context, the F1178L mutation displays a higher oncogenic potential than the R1279Q mutation as evident from a shorter latency of tumor onset. We show that tumors expressing the R1279Q mutation are sensitive to ALK inhibition upon crizotinib treatment. Furthermore, our data provide evidence that activated ALK triggers RET upregulation in mouse sympathetic ganglia at birth as well as in murine and human neuroblastoma. Using vandetanib, we show that RET inhibition strongly impairs tumor growth in vivo in both MYCN/KI AlkR1279Q and MYCN/KI AlkF1178L mice. Altogether, our findings demonstrate the critical role of activated ALK in SNS development and pathogenesis and identify RET as a therapeutic target in ALK mutated neuroblastoma.


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