Stabilization of p21 by mTORC1/4E-BP1 predicts clinical outcome of head and neck cancers

The levels, regulation and prognostic value of p21 in head and neck squamous cell carcinomas (HNSCC) has been puzzling for years. Here, we report a new mechanism of regulation of p21 by the mTORC1/4E-BP1 pathway. We find that non-phosphorylated 4E-BP1 interacts with p21 and induces its degradation. Accordingly, hyper-activation of mTORC1 results in phosphorylation of 4E-BP1 and stabilization of p21. In HNSCC, p21 levels strongly correlate with mTORC1 activity but not with p53 status. Finally, clinical data indicate that HNSCC patients with p21 and phospho-S6-double-positive tumours present a better disease-specific survival. We conclude that over-activation of the mTORC1/4E-BP1/p21 pathway is a frequent and clinically relevant alteration in HNSCC.We are grateful to Reidar Grenman, Silvio Gutkind, Nahum Sonenberg, Gordon Peters, David Sabatini and Mariano Barbacid for sharing critical reagents. We also thank Aurora Astudillo, Aitana Vallina, Laura Alonso-Dura ́n and Eva Allonca for excellent technical assistance. Work in the laboratory of M.S. is funded by the CNIO and by grants from the Spanish Ministry of Economy (SAF) co-funded by the European Regional Development Fund, the European Research Council (ERC Advanced Grant), the Regional Government of Madrid co-funded by the European Social Fund, the Botin Foundation and BancoSantander (Santander Universities Global Division), the Ramon Areces Foundation an the AXA Foundation. Work in the laboratory of J.M.G.-P. and J.P.R. was supported bygrants from Plan Nacional de DþI 2013–2016 ISCIII (CP13/00013 andPI13/00259),RD12/0036/0015 of Red Tematica de Investigacio ́n Cooperativa en Cancer (RTICC), Spain and the FEDER Funding Program from the European UnionS

Atmosphere-Space Interactions Monitor (ASIM): State of the Art

Atmosphere-Space Interactions Monitor (ASIM) mission is an ESA pay load which will be installed in the Columbus module of the International Space Station (ISS). ASIM is optimized to the observation and monitoring of luminescent phenomena in the upper atmosphere, the so called Transient Luminous Event (TLEs) and Terrestrial Gamma Ray Flashes(TGFs). Both TLEs and TGFs have been discovered recently (past two decades) and opened a new field of research in high energetic phenomena in the atmosphere. We will review the capabilities of ASIM and how it will help researchers to gain deeper knowledge of TGFs, TLEs, their inter-relationship and how they are linked to severe thunderstorms and the phenomena of lightning

A Novel Role For Nanog As An Early Cancer Risk Marker In Patients With Laryngeal Precancerous Lesions

NANOG is a master regulator of embryonic stem cell pluripotency, found to be frequently aberrantly expressed in a variety of cancers, including laryngeal carcinomas. This study investigates for the first time the role of NANOG expression in early stages of laryngeal tumourigenesis and its potential utility as cancer risk marker. NANOG protein expression was evaluated by immunohistochemistry using two large independent cohorts of patients with laryngeal precancerous lesions, and correlated with clinicopathological parameters and laryngeal cancer risk. NANOG expression was detected by immunohistochemistry in 49 (60%) of 82 laryngeal dysplasias, whereas expression was negligible in patient-matched normal epithelia. Strong NANOG expression was found in 22 (27%) lesions and was established as cut-off point, showing the most robust association with laryngeal cancer risk (P = 0.003) superior to the histological classification (P = 0.320) the current gold standard in the clinical practice. Similar trends were obtained using a multicenter validation cohort of 86 patients with laryngeal dysplasia. Our findings uncover a novel role for NANOG expression in laryngeal tumourigenesis, and its unprecedented application as biomarker for cancer risk assessment

Functional insight into the reciprocal paracrine crosstalk of stromal fibroblasts in the head and neck cancer microenvironment

Trabajo presentado en el 18th ASEICA International Congress, celebrado en Santiago de Compostela (España) del 16 al 18 de noviembre de 2022

Factors Secreted by Cancer-Associated Fibroblasts that Sustain Cancer Stem Properties in Head and Neck Squamous Carcinoma Cells as Potential Therapeutic Targets

© 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)

SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications

Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in other sarcoma subtypes. Here, we show that SOX2 depletion dramatically reduced the ability of undifferentiated pleomorphic sarcoma (UPS) cells to form tumorspheres and to initiate tumor growth. Conversely, SOX2 overexpression resulted in increased in vivo tumorigenicity. Moreover, using a reporter system (SORE6) which allows to monitor viable cells expressing SOX2 and/or OCT4, we found that SORE6+ cells were significantly more tumorigenic than the SORE6- subpopulation. In agreement with this findings, SOX2 expression in sarcoma patients was associated to tumor grade, differentiation, invasive potential and lower patient survival. Finally, we studied the effect of a panel of anti-tumor drugs on the SORE6+ cells of the UPS model and patient-derived chondrosarcoma lines. We found that the mithramycin analogue EC-8042 was the most efficient in reducing SORE6+ cells in vitro and in vivo. Overall, this study demonstrates that SOX2 is a pro-tumorigenic factor with prognostic potential in sarcoma. Moreover, SORE6 transcriptional activity is a bona fide CSC marker in sarcoma and constitutes an excellent biomarker for evaluating the efficacy of anti-tumor treatments on CSC subpopulations.This work was supported by the Agencia Estatal de Investigación (AEI) [MINECO/Fondo Europeo de Desarrollo Regional (FEDER) (SAF-2016-75286-R to R.R.), ISC III/FEDER (Miguel Servet Program CPII16/00049 to R.R., Sara Borrell Program CD16/00103 to S.T.M. and PI16/00280 and PI19/00560 to J.M.G-P) and Consorcio CIBERONC CB16/12/00390)] and the Plan de Ciencia Tecnología e Innovación del Principado de Asturias/FEDER (IDI/2018/155) to J.P.R and Predoctoral Fellowship Severo Ochoa (BP-17-108) to O.E.S