Suchergebnisse

This study was supported by grants from the Plan Nacional de I+D+I 2013-2016 ISCIII (PI13/00259), PI16/00280, and CIBERONC (CB16/12/00390) Spain, the Principado de Asturias (GRUPIN14-003), Fundación Merck Salud (17-CC-008), the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), and the FEDER Funding Program from the European Union. SAT and MAV were recipients of fellowships from ISCIII (FI12/00415 and CD13/00157, respectively). ; Álvarez-Teijeiro, S., García-Inclán, C., Villaronga, M.Á., Casado, P., Hermida-Prado, F., Granda-Díaz, R., Rodrigo, J.P., Calvo, F., Del-Río-ibisate, N., Gandarillas, A., Morís, F., Hermsen, M., Cutillas, P., García-Pedrero, J.M.

This study was supported by grants from the Plan Nacional de I+D+I 2013-2016 ISCIII PI16/00280 and CIBERONC (CB16/12/00390), Fundación Merck Salud (17-CC-008), the Instituto de Investigación Sanitariadel Principado de Asturias (ISPA), PCTI-Asturias (GRUPIN14-003), Fundación Bancaria Caja de Ahorros de Asturias-IUOPA, and the FEDER Funding Program from the European Union.

Instituto de Salud Carlos III (Spain), European Commission [PI19/01255, PI19/00560, CIBERONC CB16/12/00390]; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA); Ayudas a Grupos PCTI Principado de Asturias, Spain [IDI2018/155]; Fundación Bancaria Caja de Ahorros de Asturias-IUOPA; FEDER from the European Union

This study was supported by grants from the Plan Nacional de I+D+I 2013-2016 ISCIII (PI16/00280 and PI19/00560) to JMGP), CIBERONC (CB16/12/00390 to JPR), the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Ayudas a Grupos PCTI Principado de Asturias (IDI2018/155 to JPR), Fundación Bancaria Caja de Ahorros de Asturias-IUOPA, and the FEDER Funding Program from the European Union.

This study was supported by grants from the Plan Nacional de I+D+I 2013–2016 [ISCIII (PI19/00560 to JMGP and PI19/01353 to S.G.), CIBERONC (CB16/12/00390 to J.P.R.), the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Ayudas a Grupos PCTI Principado de Asturias (IDI2018/155 to J.P.R.), Fundación Bancaria Caja de Ahorros de Asturias-IUOPA and the FEDER Funding Program from the European Union. C.S.-B. holds a Severo Ochoa predoctoral fellowship (BP19-066).

© 2018 by the authors. ; This study investigates for the first time the crosstalk between stromal fibroblasts and cancer stem cell (CSC) biology in head and neck squamous cell carcinomas (HNSCC), with the ultimate goal of identifying effective therapeutic targets. The effects of conditioned media from cancer-associated fibroblasts (CAFs) and normal fibroblasts (NFs) on the CSC phenotype were assessed by combining functional and expression analyses in HNSCC-derived cell lines. Further characterization of CAFs and NFs secretomes by mass spectrometry was followed by pharmacologic target inhibition. We demonstrate that factors secreted by CAFs but not NFs, in the absence of serum/supplements, robustly increased anchorage-independent growth, tumorsphere formation, and CSC-marker expression. Modulators of epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR), and platelet-derived growth factor receptor (PDGFR) activity were identified as paracrine cytokines/factors differentially secreted between CAFs and NFs, in a mass spectrometry analysis. Furthermore, pharmacologic inhibition of EGFR, IGFR, and PDGFR significantly reduced CAF-induced tumorsphere formation and anchorage-independent growth suggesting a role of these receptor tyrosine kinases in sustaining the CSC phenotype. These findings provide novel insights into tumor stroma–CSC communication, and potential therapeutic targets to effectively block the CAF-enhanced CSC niche signaling circuit. ; This study was supported by grants from the Plan Nacional de I+D+I 2013-2016 ISCIII (PI13/00259), PI16/00280, and CIBERONC (CB16/12/00390) Spain, the Principado de Asturias (GRUPIN14-003), Fundación Merck Salud (17-CC-008), the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), and the FEDER Funding Program from the European Union. SAT and MAV were recipients of fellowships from ISCIII (FI12/00415 and CD13/00157, respectively).

This study was supported by grants from the Plan Nacional de I+D+I 2013-2016 ISCIII PI13/00259, PI16/00280, CIBERONC (CB16/12/00390), and MINECO/FEDER (SAF2016-75286-R), Fundación Merck Salud (17-CC-008), the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), PCTI-Asturias (GRUPIN14-003), Fundación Bancaria Caja de Ahorros de Asturias-IUOPA and the FEDER Funding Program from the European Union. STM (Sara Borrell Program - CD16/00103) and RR (Miguel Servet II Program - CPII16/00049) were recipients of fellowships from ISCIII.

This study was supported by grants from the Plan Nacional de I+D+I 2013-2016 ISCIII (PI13/00259), RD12/0036/0015 of Red Temática de Investigación Cooperativa en Cáncer (RTICC), PI16/00280, and CIBERONC(CB16/12/00390 and CB16/12/00401), CIBER-BBN (CB06/01/1031) Spain, Fundación Merck Salud (17-CC-008), the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), PCTI-Asturias (GRUPIN14-003), Fundación Bancaria Caja de Ahorros de Asturias-IUOPA, and the FEDER Funding Program from the European Union. STM (Sara Borrell Program-CD16/00103) and RR (Miguel Servet II Program-CPII16/00049) were recipients of fellowships from ISCIII.We thank the samples and technical assistance kindly provided by the Principado de Asturias BioBank (PT13/0010/0046), financed jointly by Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III and Fundación Bancaria Cajastur and integrated in the Spanish National Biobanks Network, and IIB Sant Pau. ; Hermida-Prado, Francisco J., Tirados Menendez, Sofia, Albornoz-Afanasiev, Pablo, Granda-Diaz, Rocio, Alvarez-Teijeiro, Saul, Angeles Villaronga, M., Allonca, Eva, Alonso-Duran, Laura, Leon, Xavier, Alemany, Laia, Mena, Marisa, del-Rio-Ibisate, Nagore, Astudillo, Aurora, Rodriguez, Rene, Rodrigo, Juan P., Garcia-Pedrero, Juana M.

This study was supported by grants from the Plan Nacional de I+D+I 2008–2011 Instituto de Salud Carlos III (PI11/00929 to JPR and CS) and Plan Nacional de I+D+I 2013–2016 ISCIII (CP13/00013 and PI13/00259 to JMGP), RD12/0036/0015 of Red Temática de Investigación Cooperativa en Cáncer (RTICC), Spain, and the FEDER Funding Program from the European Union. S.A.T. and M.A.V. are recipients of a fellowship from ISCIII (FI12/00415 and CD13/00157, respectively).

This study was supported by grants from the Plan Nacional de I+D+I 2013–2016 [ISCIII (PI16/00280 to JMGP and CPII16/00049 to RR), CIBERONC (CB16/12/00390 to JPR and CB16/12/00443 to LMM) and MINECO (SAF2016-75286-R to RR)], the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Fundación Merck Salud (17-CC-008 to JPR), Ayudas a Grupos PCTI Principado de Asturias (IDI2018/155 to JPR) and the FEDER Funding Program from the European Union.

This study was supported by grants from the Plan Nacional de I+D+I 2013-2016 [ISCIII (CP13/00013, PI13/00259 and PI16/00280 to JMGP and CPII16/00049 to RR), Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD12/0036/0015), CIBERONC (CB16/12/00390 to JPR and CB16/12/00443 to LM) and MINECO (SAF2013-42946-R and SAF2016-75286-R to RR)], the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), the Plan de Ciencia Tecnología e Innovación del Principado de Asturias (GRUPIN14-003 to JPR), Fundación Merck Salud (17-CC-008 to JPR), and the FEDER Funding Program from the European Union.

[Rationale]: The characterization of new genetic alterations is essential to assign effective personalized therapies in non–small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. ; [Objectives]: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. ; [Methods]: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. ; [Measurements and Main Results]: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. ; [Conclusions]: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy. ; Supported by Fundación para la Investigación Médica Aplicada (FIMA), Spanish Ministry of Economy and Innovation and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional grants 12/02040, PI13/00806, PI16/01821, PI16/00280, RTICC RD12/0036/0040, and SAF2015-6455-R; Centro de Investigación Biomédica en Red de Cáncer grants CB16/12/00390, CB16/12/00390, CB16/12/00442, and CB16/12/00443; Asociación Española Contra el Cáncer (AECC) Scientific Foundation grant GCB14-2170; Bristol-Myers Squibb (preclinical research agreement); AECC and a fellowship from the Basque Government (I.G.); the Castilla-León Government grant CSI049 U16 , the Ministry of Economy and Competitiveness grant SAF2015-64556-R , the Fundación Ramón Areces, Worldwide Cancer Research grant 14-1248 , and AECC Scientific Foundation grant GC16173472GARC (X.R.B.); and the Spanish Ministry of Science, Innovation and Universities (MCIU, RTI 2018-094507-B-100), La Caixa Foundation and Caja Navarra Foundation (F.L.). ; Peer reviewed