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

(2014) ONCOTARGET. 5(9). p.2688-2702
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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 Alk(F1178L) 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 Alk(R1279Q) and MYCN/KI Alk(F1178L) 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.
Keywords
CLASSIFICATION, PREDISPOSITION, TUMORS, PATHOGENESIS, SYSTEM, ANAPLASTIC LYMPHOMA KINASE, MYCN, MUTATIONS, CANCER, RECEPTOR TYROSINE KINASE, RET, therapeutic target, neurogenesis, ALK, Neuroblastoma

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MLA
Cazes, Alex, Lucille Lopez-Delisle, Konstantina Tsarovina, et al. “Activated Alk Triggers Prolonged Neurogenesis and Ret Upregulation Providing a Therapeutic Target in ALK-mutated Neuroblastoma.” ONCOTARGET 5.9 (2014): 2688–2702. Print.
APA
Cazes, A., Lopez-Delisle, L., Tsarovina, K., Pierre-Eugène, C., De Preter, K., Peuchmaur, M., Nicolas, A., et al. (2014). Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma. ONCOTARGET, 5(9), 2688–2702.
Chicago author-date
Cazes, Alex, Lucille Lopez-Delisle, Konstantina Tsarovina, Cécile Pierre-Eugène, Katleen De Preter, Michel Peuchmaur, André Nicolas, et al. 2014. “Activated Alk Triggers Prolonged Neurogenesis and Ret Upregulation Providing a Therapeutic Target in ALK-mutated Neuroblastoma.” Oncotarget 5 (9): 2688–2702.
Chicago author-date (all authors)
Cazes, Alex, 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, Franki Speleman, Hermann Rohrer, Olivier Delattre, and Isabelle Janoueix-Lerosey. 2014. “Activated Alk Triggers Prolonged Neurogenesis and Ret Upregulation Providing a Therapeutic Target in ALK-mutated Neuroblastoma.” Oncotarget 5 (9): 2688–2702.
Vancouver
1.
Cazes A, Lopez-Delisle L, Tsarovina K, Pierre-Eugène C, De Preter K, Peuchmaur M, et al. Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma. ONCOTARGET. 2014;5(9):2688–702.
IEEE
[1]
A. Cazes et al., “Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma,” ONCOTARGET, vol. 5, no. 9, pp. 2688–2702, 2014.
@article{5822973,
  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 Alk(F1178L) 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 Alk(R1279Q) and MYCN/KI Alk(F1178L) 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.},
  author       = {Cazes, Alex and Lopez-Delisle, Lucille and Tsarovina, Konstantina and Pierre-Eugène, Cécile and De Preter, Katleen and Peuchmaur, Michel and Nicolas, André and Provost, Claire and Louis-Brennetot, Caroline and Daveau, Romain and Kumps, Candy and Cascone, Ilaria and Schleiermacher, Gudrun and Prignon, Aurélie and Speleman, Franki and Rohrer, Hermann and Delattre, Olivier and Janoueix-Lerosey, Isabelle},
  issn         = {1949-2553},
  journal      = {ONCOTARGET},
  keywords     = {CLASSIFICATION,PREDISPOSITION,TUMORS,PATHOGENESIS,SYSTEM,ANAPLASTIC LYMPHOMA KINASE,MYCN,MUTATIONS,CANCER,RECEPTOR TYROSINE KINASE,RET,therapeutic target,neurogenesis,ALK,Neuroblastoma},
  language     = {eng},
  number       = {9},
  pages        = {2688--2702},
  title        = {Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma},
  url          = {http://dx.doi.org/10.18632/oncotarget.1883},
  volume       = {5},
  year         = {2014},
}

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