Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma : the oncogenic role of the ligands
Almazán-Moga, Anna (Hospital Universitari Vall d'Hebron)
Zarzosa, Patricia (Hospital Universitari Vall d'Hebron)
Molist, C. (Hospital Universitari Vall d'Hebron)
Velasco, Pablo (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i Medicina Preventiva i Salut Pública)
Pyczek, J. (Institute of Human Genetics, University of Goettingen)
Simon-Keller, K. (Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg)
Giralt, Irina (Hospital Universitari Vall d'Hebron)
Vidal, I (Hospital Universitari Vall d'Hebron)
Navarro, N. (Hospital Universitari Vall d'Hebron)
Segura, M. F. (Hospital Universitari Vall d'Hebron)
Soriano, Aroa (Hospital Universitari Vall d'Hebron)
Navarro, Susanna (Universitat de València. Departament de Patologia)
Tirado, O. M. (Institut d'Investigació Biomèdica de Bellvitge)
Ferreres Piñas, Joan Carles (Hospital Universitari Vall d'Hebron)
Santamaria, A. (Hospital Universitari Vall d'Hebron)
Rota, R. (Ospedale Pediatrico Bambino Gesù, IRCCS)
Hahn, H. (Institute of Human Genetics, University of Goettingen)
Sánchez de Toledo, J.. (Hospital Universitari Vall d'Hebron)
Roma, Josep (Hospital Universitari Vall d'Hebron)
Gallego, Soledad (Hospital Universitari Vall d'Hebron)

Fecha:	2017
Resumen:	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.
Ayudas:	Instituto de Salud Carlos III RTICC-RD12/0036 Instituto de Salud Carlos III RTICC-RD12/0016 Instituto de Salud Carlos III RTICC-RD12/0020 Instituto de Salud Carlos III RTICC-RD12/0053 Instituto de Salud Carlos III RTICC-RD12/0057 Instituto de Salud Carlos III PI14/00647
Nota:	Altres ajuts: This work was supported by grants from Institut Català d'Oncologia (ICO), Instituto de Salud Carlos III (RTICC-RD12/0036/0016, /0020, /0035, /0057; and PI14/00647), Fundació A BOSCH, Fundació Amics Joan Petit, ajuts predoctorals del VHIR and RIS3CAT grants COMRDI15-1-0014 (ACCIÓ and FEDER).
Nota:	Altres ajuts: FEDER/COMRDI15-1-0014
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Rhabdomyosarcoma ; Hedgehog ; Vismodegib ; UPR ; TRIB3 ; Sarcoma ; Cancer
Publicado en:	British Journal of Cancer, Vol. 117 (09 2017) , p. 1314-1325, ISSN 1532-1827

DOI: 10.1038/bjc.2017.305
PMID: 28881358

12 p, 1.7 MB

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