Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. The Hedgehog (HH) pathway is known to develop an oncogenic role in RMS. However, the molecular mechanism that drives activation of the pathway in RMS is not well understood. The expression of HH ligands was studied by...

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Detalles Bibliográficos
Autores: Almazán-Moga, Anna, Zarzosa, Patricia|||0000-0002-9711-8384, Molist, Carla|||0000-0003-3251-0083, Velasco Puyo, Pablo|||0000-0001-7331-9483, Pyczek, Joanna, Simon-Keller, Katja|||0000-0003-2340-8765, Giralt, Irina|||0000-0002-9094-4325, Vidal, Isaac, Navarro Barea, Natalia|||0000-0002-2160-6656, Segura, Miguel F.|||0000-0003-0916-3618, Soriano, Aroa|||0000-0001-9659-1471, Navarro, Susanna|||0000-0001-8160-9536, Tirado, Òscar Martínez, Ferreres Piñas, Joan Carles|||0000-0001-7742-0239, Santamaria, Anna, Rota, Rossella, Hahn, Heidi, Sánchez de Toledo Codina, José|||0000-0002-1034-1920, Roma, Josep|||0000-0001-7692-6123, Gallego, Soledad|||0000-0002-4712-9624
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:200588
Acceso en línea:https://ddd.uab.cat/record/200588
https://dx.doi.org/urn:doi:10.1038/bjc.2017.305
Access Level:acceso abierto
Palabra clave:Rhabdomyosarcoma
Hedgehog
Vismodegib
UPR
TRIB3
Sarcoma
Cancer
Descripción
Sumario:Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. The Hedgehog (HH) pathway is known to develop an oncogenic role in RMS. However, the molecular mechanism that drives activation of the pathway in RMS is not well understood. The expression of HH ligands was studied by qPCR, western blot and immunohistochemistry. Functional and animal model studies were carried out with cells transduced with shRNAs against HH ligands or treated with HH-specific inhibitors (Vismodegib and MEDI-5304). Finally, the molecular characterisation of an off-target effect of Vismodegib was also made. The results showed a prominent expression of HH ligands supporting an autocrine ligand-dependent activation of the pathway. A comparison of pharmacologic Smoothened inhibition (Vismodegib) and HH ligand blocking (MEDI-5304) is also provided. Interestingly, a first description of pernicious off-target effect of Vismodegib is also reported. The clarification of the HH pathway activation mechanism in RMS opens a door for targeted therapies against HH ligands as a possible alternative in the future development of better treatment protocols. Moreover, the description of a pernicious off-target effect of Vismodegib, via unfolded protein response activation, may mechanistically explain its previously reported inefficiency in several ligand-dependent cancers.

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