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1دورية أكاديمية
المؤلفون: Albert Grinshpun, Douglas Russo, Wen Ma, Ana Verma, Francisco Hermida-Prado, Shira Sherman, Giorgio Gaglia, Sheheryar Kabraji, Gregory Kirkner, Melissa E. Hughes, Nancy U. Lin, Zachary Sandusky, Agostina Nardone, Cristina Guarducci, Quang-De Nguyen, Sandro Santagata, Zsuzsanna Nagy, Rinath Jeselsohn
المصدر: npj Breast Cancer, Vol 10, Iss 1, Pp 1-12 (2024)
مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Abstract The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2374-4677Test
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2دورية أكاديمية
المؤلفون: Juan P. Rodrigo, Mario Sánchez-Canteli, María Otero-Rosales, Pablo Martínez-Camblor, Francisco Hermida-Prado, Juana M. García-Pedrero
المصدر: Journal of Translational Medicine, Vol 22, Iss 1, Pp 1-10 (2024)
مصطلحات موضوعية: Head and neck squamous cell carcinoma, Meta-analysis, Tumor mutational burden, Immune checkpoint inhibitors, Medicine
الوصف: Abstract Background Tumor mutational burden (TMB) has been demonstrated to predict the response to immune checkpoint inhibitors (ICIs) in various cancers. However, the role of TMB in head and neck squamous cell carcinoma (HNSCC) has not yet been specifically addressed. Since HNSCC patients exhibit a rather limited response to ICIs, there is an unmet need to develop predictive biomarkers to improve patient selection criteria and the clinical benefit of ICI treatment. Methods We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. HNSCC cohort studies were selected when TMB prior to ICI treatment was evaluated, TMB cutoff value was available, and the prognostic value of TMB was evaluated by time-to-event survival analysis. A total of 11 out of 1960 articles were analyzed, including 1200 HNSCC patients. Results The results showed that those patients harboring high TMB exhibited a significantly superior overall response rate (OR = 2.62; 95% CI 1.74–3.94; p
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/1479-5876Test
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3دورية أكاديمية
المؤلفون: Irene Montoro-Jiménez, Rocío Granda-Díaz, Sofía T. Menéndez, Llara Prieto-Fernández, María Otero-Rosales, Miguel Álvarez-González, Vanessa García-de-la-Fuente, Aida Rodríguez, Juan P. Rodrigo, Saúl Álvarez-Teijeiro, Juana M. García-Pedrero, Francisco Hermida-Prado
المصدر: International Journal of Molecular Sciences, Vol 25, Iss 5, p 2695 (2024)
مصطلحات موضوعية: SOX2, PIK3CA, 3q26 gene amplification, laryngeal tumorigenesis, cancer risk marker, dysplasia, Biology (General), QH301-705.5, Chemistry, QD1-999
الوصف: The PIK3CA and SOX2 genes map at 3q26, a chromosomal region frequently amplified in head and neck cancers, which is associated with poor prognosis. This study explores the clinical significance of PIK3CA and SOX2 gene amplification in early tumorigenesis. Gene copy number was analyzed by real-time PCR in 62 laryngeal precancerous lesions and correlated with histopathological grading and laryngeal cancer risk. Amplification of the SOX2 and PIK3CA genes was frequently detected in 19 (31%) and 32 (52%) laryngeal dysplasias, respectively, and co-amplification in 18 (29%) cases. The PIK3CA and SOX2 amplifications were predominant in high-grade dysplasias and significantly associated with laryngeal cancer risk beyond histological criteria. Multivariable Cox analysis further revealed PIK3CA gene amplification as an independent predictor of laryngeal cancer development. Interestingly, combined PIK3CA and SOX2 amplification allowed us to distinguish three cancer risk subgroups, and PIK3CA and SOX2 co-amplification was found the strongest predictor by ROC analysis. Our data demonstrate the clinical relevance of PIK3CA and SOX2 amplification in early laryngeal tumorigenesis. Remarkably, PIK3CA amplification was found to be an independent cancer predictor. Furthermore, combined PIK3CA and SOX2 amplification is emerging as a valuable and easy-to-implement tool for cancer risk assessment in patients with laryngeal precancerous lesions beyond current WHO histological grading.
وصف الملف: electronic resource
العلاقة: https://www.mdpi.com/1422-0067/25/5/2695Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test
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4دورية أكاديمية
المؤلفون: Rocío Granda-Díaz, Lorea Manterola, Francisco Hermida-Prado, René Rodríguez, Laura Santos, Vanessa García-de-la-Fuente, María Teresa Fernández, M. Daniela Corte-Torres, Juan P. Rodrigo, Saúl Álvarez-Teijeiro, Charles H. Lawrie, Juana M. Garcia-Pedrero
المصدر: Biomedicine & Pharmacotherapy, Vol 161, Iss , Pp 114512- (2023)
مصطلحات موضوعية: Head and neck squamous cell carcinoma, miR-301a, Therapeutic target, Signaling, PI3K, ERK, Therapeutics. Pharmacology, RM1-950
الوصف: Treatment of head and neck squamous cell carcinomas (HNSCC), the sixth most frequent cancer worldwide, remains challenging. miRNA dysregulation is closely linked to tumorigenesis and tumor progression, thus emerging as suitable targets for cancer treatment. Transcriptomic analysis of TCGA HNSCC dataset revealed that miR-301a expression levels significantly increased in primary tumors, as compared to patient-matched normal tissue. This prompted us to investigate its pathobiological role and potential as new therapeutic target using different preclinical HNSCC models. miR-301a overexpression in HNSCC-derived cell lines led to enhanced proliferation and invasion, whereas miR-301 inhibition reduced these effects. In vivo validation was performed using an orthotopic mouse model. Results concordantly showed that the mitotic counts, the percentage of infiltration depth and Ki67 proliferative index were significantly augmented in the subgroup of mice harboring miR-301a-overexpressing tumors. Further mechanistic characterization revealed PI3K/PTEN/AKT and MEK/ERK pathways as central signaling nodes responsible for mediating the oncogenic activity of miR-301a observed in HNSCC cells. Notably, pharmacological disruption of PI3K and ERK signals with BYL-719 and PD98059, respectively, was effective to completely revert/abolish miR-301a-promoted tumor cell growth and invasion. Altogether, these findings demonstrate that miR-301a dysregulation plays an oncogenic role in HNSCC, thus emerging as a candidate therapeutic target for this disease. Importantly, available PI3K and ERK inhibitors emerge as promising anti-tumor agents to effectively target miR-301a-mediated signal circuit hampering growth-promoting and pro-invasive functions.
وصف الملف: electronic resource
العلاقة: http://www.sciencedirect.com/science/article/pii/S0753332223003001Test; https://doaj.org/toc/0753-3322Test
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5دورية أكاديمية
المؤلفون: Llara Prieto-Fernandez, Maria de los Angeles Villaronga, Francisco Hermida-Prado, Maruan Hijazi, Irene Montoro-Jimenez, Marta Pevida, Sara Llames, Juan Pablo Rodrigo, Pedro Cutillas, Fernando Calvo, Juana Maria Garcia-Pedrero, Saul Alvarez-Teijeiro
المصدر: Biomedicine & Pharmacotherapy, Vol 158, Iss , Pp 114176- (2023)
مصطلحات موضوعية: Head and neck cancer, Invasion, Stromal fibroblasts, Cancer-associated fibroblasts, Phosphoproteomics, Therapeutics. Pharmacology, RM1-950
الوصف: Background: Cancer-associated fibroblasts (CAFs) are major players in tumor-stroma communication, and participate in several cancer hallmarks to drive tumor progression and metastatic dissemination. This study investigates the driving effects of tumor-secreted factors on CAF biology, with the ultimate goal of identifying effective therapeutic targets/strategies for head and neck squamous cell carcinomas (HNSCC). Methods: Functionally, conditioned media (CM) from different HNSCC-derived cell lines and normal keratinocytes (Kc) were tested on the growth and invasion of populations of primary CAFs and normal fibroblasts (NFs) using 3D invasion assays in collagen matrices. The changes in MMPs expression were evaluated by RT-qPCR and kinase enrichment was analyzed using mass spectrometry phosphoproteomics. Results: Our results consistently demonstrate that HNSCC-secreted factors (but not Kc CM) specifically and robustly promoted pro-invasive properties in both CAFs and NFs, thereby reflecting the plasticity of fibroblast subtypes. Concomitantly, HNSCC-secreted factors massively increased metalloproteinases levels in CAFs and NFs. By contrast, HNSCC CM and Kc CM exhibited comparable growth-promoting effects on stromal fibroblasts. Mechanistically, phosphoproteomic analysis predominantly revealed phosphorylation changes in fibroblasts upon treatment with HNSCC CM, and various promising kinases were identified: MKK7, MKK4, ASK1, RAF1, BRAF, ARAF, COT, PDK1, RSK2 and AKT1. Interestingly, pharmacologic inhibition of RAF1/BRAF using sorafenib emerged as the most effective drug to block tumor-promoted fibroblast invasion without affecting fibroblast viability Conclusions: Our findings demonstrate that HNSCC-secreted factors specifically fine tune the invasive potential of stromal fibroblasts, thereby generating tumor-driven pro-invasive niches, which in turn to ultimately facilitate cancer cell dissemination. Furthermore, the RAF/BRAF inhibitor sorafenib was identified as a promising candidate to effectively target the onset of pro-invasive clusters of stromal fibroblasts in the HNSCC microenvironment.
وصف الملف: electronic resource
العلاقة: http://www.sciencedirect.com/science/article/pii/S0753332222015657Test; https://doaj.org/toc/0753-3322Test
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6دورية أكاديمية
المؤلفون: Llara Prieto-Fernández, Sofía T. Menéndez, María Otero-Rosales, Irene Montoro-Jiménez, Francisco Hermida-Prado, Juana M. García-Pedrero, Saúl Álvarez-Teijeiro
المصدر: Frontiers in Cell and Developmental Biology, Vol 10 (2022)
مصطلحات موضوعية: annexin, head and neck cancer, biomarker, diagnosis, therapeutic target, Biology (General), QH301-705.5
الوصف: Annexins are an extensive superfamily of structurally related calcium- and phospholipid-binding proteins, largely conserved and widely distributed among species. Twelve human annexins have been identified, referred to as Annexin A1-13 (A12 remains as of yet unassigned), whose genes are spread throughout the genome on eight different chromosomes. According to their distinct tissue distribution and subcellular localization, annexins have been functionally implicated in a variety of biological processes relevant to both physiological and pathological conditions. Dysregulation of annexin expression patterns and functions has been revealed as a common feature in multiple cancers, thereby emerging as potential biomarkers and molecular targets for clinical application. Nevertheless, translation of this knowledge to the clinic requires in-depth functional and mechanistic characterization of dysregulated annexins for each individual cancer type, since each protein exhibits varying expression levels and phenotypic specificity depending on the tumor types. This review specifically and thoroughly examines the current knowledge on annexin dysfunctions in carcinogenesis. Hence, available data on expression levels, mechanism of action and pathophysiological effects of Annexin A1-13 among different cancers will be dissected, also further discussing future perspectives for potential applications as biomarkers for early diagnosis, prognosis and molecular-targeted therapies. Special attention is devoted to head and neck cancers (HNC), a complex and heterogeneous group of aggressive malignancies, often lately diagnosed, with high mortality, and scarce therapeutic options.
وصف الملف: electronic resource
العلاقة: https://www.frontiersin.org/articles/10.3389/fcell.2022.1009908/fullTest; https://doaj.org/toc/2296-634XTest
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7دورية أكاديمية
المؤلفون: Konstantinos Tzelepis, Etienne De Braekeleer, Demetrios Aspris, Isaia Barbieri, M. S. Vijayabaskar, Wen-Hsin Liu, Malgorzata Gozdecka, Emmanouil Metzakopian, Hamish D. Toop, Monika Dudek, Samuel C. Robson, Francisco Hermida-Prado, Yu Hsuen Yang, Roya Babaei-Jadidi, Dimitrios A. Garyfallos, Hannes Ponstingl, Joao M. L. Dias, Paolo Gallipoli, Michael Seiler, Silvia Buonamici, Binje Vick, Andrew J. Bannister, Roland Rad, Rab K. Prinjha, John C. Marioni, Brian Huntly, Jennifer Batson, Jonathan C. Morris, Cristina Pina, Allan Bradley, Irmela Jeremias, David O. Bates, Kosuke Yusa, Tony Kouzarides, George S. Vassiliou
المصدر: Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018)
مصطلحات موضوعية: Science
الوصف: SRPK1, a kinase involved in splicing regulation, is a potential therapeutic target for AML patients. Here, the authors show that SRPK1 inhibition changes isoform levels of key epigenetic regulators, including BRD4, and it has anti-tumor effects specifically against MLL-rearranged AML cells.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2041-1723Test
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8دورية أكاديمية
المؤلفون: Juan Tornin, Francisco Hermida-Prado, Ranjit Singh Padda, M. Victoria Gonzalez, Carlos Alvarez-Fernandez, Veronica Rey, Lucia Martinez-Cruzado, Oscar Estupiñan, Sofia T. Menendez, Lucia Fernandez-Nevado, Aurora Astudillo, Juan P. Rodrigo, Fabrice Lucien, Yohan Kim, Hon S. Leong, Juana Maria Garcia-Pedrero, Rene Rodriguez
المصدر: Neoplasia: An International Journal for Oncology Research, Vol 20, Iss 1, Pp 44-56 (2018)
مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP–mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP–expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP–mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatment.
وصف الملف: electronic resource
العلاقة: http://www.sciencedirect.com/science/article/pii/S1476558617303585Test; https://doaj.org/toc/1476-5586Test; https://doaj.org/toc/1522-8002Test
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9دورية أكاديمية
المؤلفون: Faustino Julián Suárez-Sánchez, Paloma Lequerica-Fernández, Juan Pablo Rodrigo, Francisco Hermida-Prado, Julián Suárez-Canto, Tania Rodríguez-Santamarta, Francisco Domínguez-Iglesias, Juana M. García-Pedrero, Juan Carlos de Vicente
المصدر: Cancers, Vol 13, Iss 3, p 395 (2021)
مصطلحات موضوعية: CD20, tumor-infiltrating B lymphocytes, prognosis, oral squamous cell carcinoma, immunohistochemistry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Immunohistochemical analysis of stromal/tumoral CD20+ B lymphocytes was performed in 125 OSCC patients. Correlations with immune profiles CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocytes (TILs), tumoral PD-L1, and stem-related factors NANOG and SOX2 were assessed, and also associations with clinical data and patient survival. There was a strong positive correlation between the infiltration of CD20+ B lymphocytes and other immune profiles (i.e., CD4+, CD8+, and FOXP3+ TILs, and CD68+ and CD163+ macrophages) both in stroma and tumor nests. Strikingly, CD20+ TILs were inversely correlated with NANOG/SOX2 expression. Stromal CD20+ TILs were significantly associated with T classification and second primary tumors. A stratified survival analysis showed that tumoral CD20+ TILs were significantly associated with prognosis in male and younger patients, with tobacco or alcohol consumption, high tumoral CD8+ TILs, low tumoral infiltration by CD68+ macrophages, positive PD-L1 expression, and negative NANOG/SOX2. Multivariate Cox analysis further revealed clinical stage and tumoral CD20+ TILs independently associated with disease-specific survival (HR = 2.42, p = 0.003; and HR = 0.57, p = 0.04, respectively). In conclusion, high CD20+ TIL density emerges as an independent good prognostic factor in OSCC, suggesting a role in antitumor immunity. This study also uncovered an inverse correlation between CD20+ TILs and CSC marker expression.
وصف الملف: electronic resource
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10دورية أكاديمية
المؤلفون: Mario Sanchez-Canteli, Francisco Hermida-Prado, Christian Sordo-Bahamonde, Irene Montoro-Jiménez, Esperanza Pozo-Agundo, Eva Allonca, Aitana Vallina-Álvarez, César Álvarez-Marcos, Segundo Gonzalez, Juana M. García-Pedrero, Juan P. Rodrigo
المصدر: Biomedicines, Vol 8, Iss 12, p 535 (2020)
مصطلحات موضوعية: lectin-like transcript 1, LLT1, CLEC2D, immune checkpoint, NK cell, head and neck squamous cell carcinomas, Biology (General), QH301-705.5
الوصف: Lectin-like transcript 1 (LLT1) expression by tumor cells contributes to immune evasion, thereby emerging as a natural killer (NK) cell-mediated immunotherapeutic target. This study is the first to investigate LLT1 expression (encoded by CLEC2D gene) in head and neck cancers to ascertain its impact on patient prognosis. LLT1 expression was analyzed by immunohistochemistry in a homogeneous cohort of human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinomas (OPSCC), and correlated with clinical data. Results were further validated using transcriptomic data from the TCGA database. Tumoral LLT1 expression was detected in 190/221 (86%) OPSCC specimens, whereas normal pharyngeal epithelium was negative. Patients harboring LLT1-positive tumors showed significantly lower disease-specific (DSS) and overall survival (OS) (p = 0.049 and p = 0.036, respectively, log-rank test). High density of LLT1-positive tumor-infiltrating lymphocytes (TIL) was also frequently detected in 160 (73%) OPSCC samples, and significantly associated with better DSS and OS (p < 0.001 and p = 0.007, respectively). Multivariate Cox analysis further revealed that tumoral LLT1 expression and infiltration of LLT1-positive TIL were independent prognostic factors for DSS and OS. CLEC2D mRNA levels are also significantly increased in primary tumors compared to normal tissue. Strikingly, the prognostic impact of CLEC2D mRNA levels varied depending on HPV status in OPSCC, and among distinct cancer types. CLEC2D expression was significantly correlated with NK cell infiltration using the MCP-counter model. These findings uncover LLT1/CLEC2D as an independent prognostic factor in HPV-negative OPSCC, and a potential novel target for immunotherapy.
وصف الملف: electronic resource
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