Examinando por Autor "Martinez-Useros, Javier"

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A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma
(National Academy of Sciences of the United States of America, 2011-07-11) Beltran, Elena; Fresquet, Vicente; Martinez-Useros, Javier; Richter-Larrea, Jose A.; Sagardoy, Ainara; Sesma, Izaskun; Almada, Luciana L.; Montes-Serrano, Santiago; Siebert, Reiner; Gesk, Stefan; Calasanz, María J.; Malumbres, Raquel; Rieger, Melissa; Prosper, Felipe; Lossos, Izidore S.; Piris, Miguel Angel; Fernandez-Zapico, Martin E.; Martinez-Climent, Jose A.
The chromosomal translocationt(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development ofmantle cell lymphoma (MCL), an aggressive tumor that remains in-curable with current treatment strategies. Cyclin-D1 has been pos-tulated as an effective therapeutic target, but the evaluation of thistarget has been hampered by our incomplete understanding of itsoncogenic functions and by the lack of valid MCL murine models. Toaddress these issues, we generated a cyclin-D1–driven mouse modelin which cyclin-D1 expression can be regulated externally. Thesemice developed cyclin-D1–expressing lymphomas capable of recapit-ulating features of human MCL. We found that cyclin-D1 inactiva-tion was not sufficient to induce lymphoma regression in vivo;however, using a combination of in vitro and in vivo assays, weidentified a novel prosurvival cyclin-D1 function in MCL cells. Specif-ically, we found that cyclin-D1, besides increasing cell proliferationthrough deregulation of the cell cycle at the G1–S transition, seques-trates the proapoptotic protein BAX in the cytoplasm, thereby fa-voring BCL2’s antiapoptotic function. Accordingly, cyclin-D1 inhi-bition sensitized the lymphoma cells to apoptosis through BAXrelease. Thus, genetic or pharmacologic targeting of cyclin-D1 com-bined with a proapoptotic BH3 mimetic synergistically killed thecyclin-D1–expressing murine lymphomas, human MCL cell lines,and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the poten-tial benefit of simultaneously targeting cyclin-D1 and survival path-ways in patients with MCL. This effective combination therapy alsomight be exploited in other cyclin-D1–expressing tumors.
Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy
(Nature Publishing Group, 2014-05-27) del Puerto-Nevado, Laura; Rojo, Federico; Zazo, Sandra; Carames, Cristina; Rubio, Gustavo; Vega, Ricardo; Chamizo, Cristina; Casado, Victoria; Martinez-Useros, Javier; Rincón, Raul; Rodríguez-Remírez, Maria; Borrero-Palacios, Aurea; Cristobal, Ion; Madoz-Gúrpide, Juan; Aguilera, Oscar; García-Foncillas, Jesus
Background: Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients. Methods: Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out. Results: The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10–300); for KDR 258.5 (range, 150–300); for pKDRY1775 10.8 (range, 0–65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10–126). Statistical differences for PFS (P = 0.01) and OS (P = 0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDRY1775 expression remained significant after multivariate Cox analysis for PFS (P = 0.01; HR: 5.35, 95% CI, 1.49–19.13) and for OS (P = 0.02; HR: 5.13, 95% CI, 1.25–21.05). Conclusions: Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.
High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma
(Blackwell Publishing, 2012-07-23) Fresquet, Vicente; Robles, Eloy F.; Parker, Anton; Martinez-Useros, Javier; Mena, Maria; Malumbres, Raquel; Agirre, Xabier; Catarino, Susana; Arteta, David; Osaba, Lourdes; Mollejo, Manuela; Hernandez-Rivas, Jesus M.; Calasanz, María José; Daibata, Masanori; Dyer, Martin J. S.; Prosper, Felipe; Vizcarra, Esperanza; Piris, Miguel A.; Oscier, David; Martinez-Climent, Jose A.
Using high-resolution genomic microarray analysis, a distinct genomic pro-file was defined in 114 samples from patients with splenic marginal zonelymphoma (SMZL). Deletion or uniparental disomy of chromosome 7qwere detected in 42 of 114 (37%) SMZLs but in only nine of 170 (5%)mature B-cell lymphomas (P<0 00001). The presence of unmutatedIGHV, genomic complexity, 17p13-TP53deletion and 8q-MYCgain, butnot 7q deletion, correlated with shorter overall survival of SMZL patients.Mapping studies narrowed down a commonly deleted region of 2 7Mbin7q32.1-q32.2 spanning a region between theSND1andCOPG2genes.High-throughput sequencing analysis of the 7q32-deleted segment did notidentify biallelic deletions/insertions or clear pathogenic gene mutations,but detected six nucleotide changes inIRF5(n=2),TMEM209(n=2),CALU(n=1) andZC3HC1(n=1) not found in healthy individuals.Comparative expression analysis found a fourfold down-regulation ofIRF5gene in lymphomas with 7q32 deletionversusnon-deleted tumours(P=0 032). Ectopic expression of IRF5 in marginal-zone lymphoma cellsdecreased proliferation and increased apoptosisin vitro, and impaired lym-phoma developmentin vivo. These results show that cryptic deletions,insertions and/or point mutations inactivating genes within 7q32 are notcommon in SMZL, and suggest that IRF5 may be a haploinsufficienttumour suppressor in this lymphoma entity.
KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study
(MDPI, 2020-01-15) Garcia-Carbonero, Nuria; Martinez-Useros, Javier; Li, Weiyao; Orta, Alberto; Perez, Nuria; Carames, Cristina; Hernandez, Tatiana; Moreno, Irene; Serrano, Gloria; García-Foncillas, Jesus
KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086–2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110–2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531–13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.
The challenge of blocking a wider family members of EGFR against head and neck squamous cell carcinomas
(Elsevier, 2015-03-06) Martinez-Useros, Javier; García-Foncillas, Jesus
Head and neck squamous cell carcinoma (HNSCC) represent 95% of head and neck cancer with an incidence of over half a million people globally. The prognosis for patients with recurrent or metastatic HNSCC is generally poor with low 5-year survival rates despite treatment advances over the past few decades. Consequently, it is essential to search for new biomarkers and effective therapy options to optimize HNSCC treatment. Epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of tumours. EGFR has become one of most common targets for new therapies being investigated in HNSCC. In this way, multiple therapies targeting EGFR in HNSCC have been tested but response rates are still low especially in the recurrent or metastatic setting. This has been attributed to mechanisms of resistance to EGFR-targeted therapies. Afatinib, an oral small molecule ErbB Family Blocker that irreversibly binds to ErbB1 (EGFR), ErbB2 (HER2) and ErbB4 (HER4), is being investigated in HNSCC treatment with encouraging phase II results and several ongoing phase III trials. Results of these trials will help to understand the place of afatinib in the HNSCC treatment armamentarium.
The Clinical Significance of PIWIL3 and PIWIL4 Expression in Pancreatic Cancer
(MDPI, 2020-04-26) Li, Weiyao; Martinez-Useros, Javier; Garcia-Carbonero, Nuria; Fernández-Aceñero, María Jesús; Orta, Alberto; Ortega-Medina, Luis; Garcia-Botella, Sandra; Perez-Aguirre, Elia; Diez-Valladares, Luis; Celdrán, Ángel; García-Foncillas, Jesus
P-element-induced wimpy testis (PIWI) proteins have been described in several cancers. PIWIL1 and PIWIL2 have been recently evaluated in pancreatic cancer, and elevated expression of PIWIL2 conferred longer survival to patients. However, PIWIL3’s and PIWIL4’s role in carcinogenesis is rather controversial, and their clinical implication in pancreatic cancer has not yet been investigated. In the present study, we evaluated PIWIL1, PIWIL2, PIWIL3 and PIWIL4 expression in pancreatic cancer-derived cell lines and in one non-tumor cell line as healthy control. Here, we show a di erential expression in tumor and non-tumor cell lines of PIWIL3 and PIWIL4. Subsequently, functional experiments with PIWIL3 and/or PIWIL4 knockdown revealed a decrease in the motility ratio of tumor and non-tumor cell lines through downregulation of mesenchymal factors in pro of epithelial factors. We also observed that PIWIL3 and/or PIWIL4 silencing impaired undi erentiated phenotype and enhanced drug toxicity in both tumor- and non-tumor-derived cell lines. Finally, PIWIL3 and PIWIL4 evaluation in human pancreatic cancer samples showed that patients with low levels of PIWIL4 protein expression presented poor prognosis. Therefore, PIWIL3 and PIWIL4 proteins may play crucial roles to keep pancreatic cell homeostasis not only in tumors but also in healthy tissues
UNR/ CSDE1 Expression Is Critical to Maintain Invasive Phenotype of Colorectal Cancer through Regulation of c-MYC and Epithelial-to-Mesenchymal Transition
(MDPI, 2019-04-25) Martinez-Useros, Javier; Garcia-Carbonero, Nuria; Li, Weiyao; Fernández-Aceñero, María Jesús; Cristobal, Ion; Rincón, Raul; Rodríguez-Remírez, Maria; Borrero-Palacios, Aurea; García-Foncillas, Jesus
CSDE1 (cold shock domain containing E1) gene is located upstream of the N-RAS locus, and codes for an RNA-binding protein named Upstream of N-Ras (UNR). In cancer, CSDE1 has been shown to regulate c-Fos, c-Myc, Pten, Rac1, or Vimentin. UNR/CSDE1 has been studied in breast, melanoma, pancreatic and prostate cancer. Then, the aim of this study is to evaluate the role of CSDE1/UNR in colorectal cancer progression and maintenance of aggressive phenotype. We firstly evaluated UNR/CSDE1 expression in human colon cancer derived cell lines and patient samples. Subsequently, we performed functional experiments by UNR/CSDE1 downregulation. We also evaluated UNR/CSDE1 prognostic relevance in two independent sets of patients. Not only was UNR/CSDE1 expression higher in tumor samples compared to untransformed samples, but also in colonospheres and metastatic origin cell lines than their parental and primary cell lines, respectively. Downregulation of UNR/CSDE1 reduced cell viability and migration throughout a restrain of epithelial-to-mesenchymal transition and increases sensitivity to apoptosis. Interestingly, high UNR/CSDE1 expression was associated with poor prognosis and correlated positively with c-MYC expression in colorectal cancer samples and cell lines. Here, we show for the first time compelling data reporting the oncogenic role of UNR/CSDE1 in human colorectal cancer.
UNR/CDSE1 expression as prognosis biomarker in resectable pancreatic ductal adenocarcinoma patients: A proof-of-concept
(PLOS, 2017-08-01) Martinez-Useros, Javier; Georgiev-Hristov, Tihomir; Fernández-Aceñero, María Jesús; Borrero-Palacios, Aurea; Indacochea, Alberto; Guerrero, Santiago; Li, Weiyao; Cebrian, Arancha; Gomez del Pulgar, Teresa; Puime-Otin, Alberto; del Puerto-Nevado, Laura; Rodríguez-Remírez, Maria; Perez, Nuria; Celdrán, Ángel; Gebauer, Fatima; García-Foncillas, Jesus
Pancreatic ductal adenocarcinoma is an aggressive form of pancreatic cancer and the fourth leading cause of cancer-related death. When possible, curative approaches are based on surgical resection, though not every patient is a candidate for surgery. There are clinical guidelines for the management of these patients that offer different treatment options depending on the clinical and pathologic characteristics. However, the survival rates seen in this kind of patients are still low. The CDSE1 gene is located upstream of NRAS and encodes an RNA-binding protein termed UNR. The aim of this study was to analyze UNR expression and its correlation with outcome in patients with resectable pancreatic ductal adenocarcinoma (PDAC). For this, samples from resectable PDAC patients who underwent duodenopancreatectomy were used to evaluate UNR protein expression by immunohistochemistry using a tissue microarray. Here, we observed that low UNR expression was significantly associated with shorter progression-free survival after surgery (P = 0.010). Moreover, this prognostic marker remained significant after Cox proportional hazards model (P = 0.036). We further studied the role of CDSE1 expression in patient's prognosis using data from public repositories (GEO and TGCA), confirming our results. Interestingly, CDSE1 expression correlated with that of genes characteristic of an immunogenic molecular subtype of pancreatic cancer. Based on these findings, UNR may be considered a potential prognostic biomarker for resectable PDAC and may serve to guide subsequent adjuvant treatment decisions.
UNR/CSDE1 Drives a Post-transcriptional Program to Promote Melanoma Invasion and Metastasis
(CellPress, 2016-11-14) Wurth, Laurence; Papasaikas, Panagiotis; Olmeda, David; Bley, Nadine; Calvo, Guadalupe T.; Guerrero, Santiago; Cerezo-Wallis, Daniela; Martinez-Useros, Javier; García-Fernández, Maria; Hüttelmaier, Stefan; Soengas, Marisol; Gebauer, Fatima
RNA binding proteins (RBPs) modulate cancer progression through poorly understood mechanisms. Here we show that the RBP UNR/CSDE1 is overexpressed in melanoma tumors and promotes invasion and metastasis. iCLIP sequencing, RNA sequencing, and ribosome profiling combined with in silico studies unveiled sets of pro-metastatic factors coordinately regulated by UNR as part of RNA regulons. In addition to RNA steady-state levels, UNR was found to control many of its targets at the level of translation elongation/termination. Key pro-oncogenic targets of UNR included VIM and RAC1, as validated by loss- and gain-of-function studies. Our results identify UNR as an oncogenic modulator of melanoma progression, unravel the underlying molecular mechanisms, and identify potential targets for this therapeutically challenging malignancy