Montuenga-Badia, L.M. (Luis M.)
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- DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies CREBBP as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC)(2020) Cendoya-Garmendia, X. (Xabier); Pio, R. (Rubén); Serrano, D. (Diego); Castilla, C. (Carlos); Campuzano, L. (Lucía); Carazo-Melo, F.(Fernando); Montuenga-Badia, L.M. (Luis M.); Bertolo, C. (Cristina); Planes-Pedreño, F.J. (Francisco Javier); Gimeno-Combarro, M. (Marian); Rubio, A. (Ángel)The development of predictive biomarkers of response to targeted therapies is an unmet clinical need for many antitumoral agents. Recent genome-wide loss-of-function screens, such as RNA interference (RNAi) and CRISPR-Cas9 libraries, are an unprecedented resource to identify novel drug targets, reposition drugs and associate predictive biomarkers in the context of precision oncology. In this work, we have developed and validated a large-scale bioinformatics tool named DrugSniper, which exploits loss-of-function experiments to model the sensitivity of 6237 inhibitors and predict their corresponding biomarkers of sensitivity in 30 tumor types. Applying DrugSniper to small cell lung cancer (SCLC), we identified genes extensively explored in SCLC, such as Aurora kinases or epigenetic agents. Interestingly, the analysis suggested a remarkable vulnerability to polo-like kinase 1 (PLK1) inhibition in CREBBP-mutant SCLC cells. We validated this association in vitro using four mutated and four wild-type SCLC cell lines and two PLK1 inhibitors (Volasertib and BI2536), confirming that the effect of PLK1 inhibitors depended on the mutational status of CREBBP. Besides, DrugSniper was validated in-silico with several known clinically-used treatments, including the sensitivity of Tyrosine Kinase Inhibitors (TKIs) and Vemurafenib to FLT3 and BRAF mutant cells, respectively. These findings show the potential of genome-wide loss-of-function screens to identify new personalized therapeutic hypotheses in SCLC and potentially in other tumors, which is a valuable starting point for further drug development and drug repositioning projects.
- Complement activation mediates cetuximab inhibition of non-small cell lung cancer tumor growth in vivo(Biomed Central, 2010-06) Pio, R. (Rubén); Lopez-Picazo, J.M. (José M.); Corrales, L. (Leticia); Hsu, Y.F. (Y. F.); Gurpide, A. (Alfonso); Montuenga-Badia, L.M. (Luis M.); Ajona, D. (Daniel)Background Cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), increases survival in patients with advanced EGFR-positive non-small cell lung cancer when administrated in combination with chemotherapy. In this study, we investigated the role of complement activation in the antitumor mechanism of this therapeutic drug. Results EGFR-expressing lung cancer cell lines were able to bind cetuximab and initiate complement activation by the classical pathway, irrespective of the mutational status of EGFR. This activation led to deposition of complement components and increase in complement-mediated cell death. The influence of complement activation on the activity of cetuximab in vivo was evaluated in xenografts of A549 lung cancer cells on nude mice. A549 cells express wild-type EGFR and have a KRAS mutation. Cetuximab activity against A549 xenografts was highly dependent on complement activation, since complement depletion completely abrogated the antitumor efficacy of cetuximab. Moreover, cetuximab activity was significantly higher on A549 cells in which a complement inhibitor, factor H, was genetically downregulated. Conclusions We demonstrate for the first time that the in vivo antitumor activity of cetuximab can be associated with a complement-mediated immune response. These results may have important implications for the development of new cetuximab-based therapeutic strategies and for the identification of markers that predict clinical response.
- Consensus statements from the Second International Lung Cancer Molecular Biomarkers Workshop: a European strategy for developing lung cancer molecular diagnostics in high risk populations(Spandidos Publications, 2002) Tockman, M. (M.); Pullen, J. (J.); Lachmann, P. (P.); Herman, J. (J.); Tyndale, R. (R.); Field, J.K. (J. K.); Henschke, C.I. (C.I.); Maier, S. (S.); Youngson, J. (J.); Mulshine, J.L. (James L.); Montuenga-Badia, L.M. (Luis M.); Murphy, M. (Murphy); Caporaso, N.E. (Neil E.); Spitz, M.R. (Margaret R.); Lam, S. (S.); Wistuba, I.I. (Ignacio I.); Hirsch, F. (F.); Flahault, A. (A.); Brambilla, C. (C.)The Second Molecular Biomarkers Workshop was held at the Roy Castle International Centre for Lung Cancer Research in Liverpool, in June 2001 and it brought together experts in the clinical, epidemiological and molecular-pathology of lung cancer from Europe and the USA, to address issues surrounding the development of a European strategy for early lung cancer detection. The 2001 Workshop Breakout Groups concentrated on the current challenges in the early detection of lung cancer which need to be addressed in the light of the recent surge in interest in many countries for mounting new clinical trials to evaluate the utility of Spiral CT in early lung cancer detection. If population-based trials of CT screening are mounted it will also be a favorable clinical environment in which to evaluate efficiently recent advances in molecular screening and genotyping. The Workshop focused specifically on: a) clinical and molecular biomarkers, b) sputum as an early detection and diagnostic tool, c) validation of molecular markers prior to their use in early detection trials and d) ethical issues that have to be considered in early lung cancer detection trials. A distillation of the Workshop discussions is given in this article.
- Development of a novel splice array platform and its application in the identification of alternative splice variants in lung cancer(BioMed Central, 2010-06-03) Pajares, M.J. (María José); Anton, M.A. (Miguel Ángel); Pio, R. (Rubén); Lozano, M.D. (María Dolores); Gomez-Roman, J. (Javier); Agorreta, J. (Jackeline); Subirada, F. (Francesc); Durany, O. (O.); Lopez-Picazo, J.M. (José M.); Blanco, D. (Daniel); Ezponda, T. (Teresa); Montuenga-Badia, L.M. (Luis M.); Aibar, E. (Elena); Maes, T. (Tamara); Rubio, A. (Ángel)Abstract Background Microarrays strategies, which allow for the characterization of thousands of alternative splice forms in a single test, can be applied to identify differential alternative splicing events. In this study, a novel splice array approach was developed, including the design of a high-density oligonucleotide array, a labeling procedure, and an algorithm to identify splice events. Results The array consisted of exon probes and thermodynamically balanced junction probes. Suboptimal probes were tagged and considered in the final analysis. An unbiased labeling protocol was developed using random primers. The algorithm used to distinguish changes in expression from changes in splicing was calibrated using internal non-spliced control sequences. The performance of this splice array was validated with artificial constructs for CDC6, VEGF, and PCBP4 isoforms. The platform was then applied to the analysis of differential splice forms in lung cancer samples compared to matched normal lung tissue. Overexpression of splice isoforms was identified for genes encoding CEACAM1, FHL-1, MLPH, and SUSD2. None of these splicing isoforms had been previously associated with lung cancer. Conclusions This methodology enables the detection of alternative splicing events in complex biological samples, providing a powerful tool to identify novel diagnostic and prognostic biomarkers for cancer and other pathologies.
- Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis(Endocrine Society, 2000) Gassmann, M. (Max); Pio, R. (Rubén); Garayoa, M. (Mercedes); Ryan, H. (Heather); An, W.G. (Won G.); Neckers, L. (Len); Montuenga-Badia, L.M. (Luis M.); Johnson, R. (Randall); Lee, S. (Sunmin); Cuttitta, F. (Frank); Martinez, A. (Alfredo); Trepel, J. (Jane)Little is known about the molecular mechanisms that control adrenomedullin (AM) production in human cancers. We demonstrate here that the expression of AM mRNA in a variety of human tumor cell lines is highly induced in a time-dependent manner by reduced oxygen tension (1% O2) or exposure to hypoxia mimetics such as desferrioxamine mesylate (DFX) or CoCl2. This AM expression seems to be under hypoxia-inducible factor-1 (HIF-1) transcriptional regulation, since HIF-1alpha and HIF-1beta knockout mouse cell lines had an ablated or greatly reduced hypoxia AM mRNA induction. Similarly, inhibition or enhancement of HIF-1 activity in human tumor cells showed an analogous modulation of AM mRNA. Under hypoxic conditions, immunohistochemical analysis of tumor cell lines revealed elevated levels of AM and HIF-1alpha as compared with normoxia, and we also found an increase of immunoreactive AM in the conditioned medium of tumor cells analyzed by RIA. AM mRNA stabilization was shown to be partially responsible for the hypoxic up-regulated expression of AM. In addition, we have identified several putative hypoxia response elements (HREs) in the human AM gene, and reporter studies with selected HREs were capable of enhancing luciferase expression after exposure to DFX. Furthermore, transient coexpression of HIF-1alpha resulted in an augmented transactivation of the reporter gene after DFX treatment. Given that most solid human tumors have focal hypoxic areas and that AM functions as a mitogen, angiogenic factor, and apoptosis-survival factor, our findings implicate the HIF-1/AM link as a possible promotion mechanism of carcinogenesis.
- Comprehensive Analysis of SWI/SNF Inactivation in Lung Adenocarcinoma Cell Models(2020) Patiño-Mercau, J.R. (Juan Rodrigo); Álvarez-Perez, J.C. (Juan Carlos); Romero, O.A. (Octavio A.); Medina, P.P. (Pedro P.); Coira, I.F. (Isabel F.); Cuadros, M. (Marta); Rodriguez, M.I. (Maria Isabel); Arenas, A.M. (Alberto M.); Andrades, A. (Alvaro); Montuenga-Badia, L.M. (Luis M.); Sanjuan-Hidalgo, J. (Juan); Baliñas-Gavira, C. (Carlos); Sanchez-Cespedes, M. (Montserrat); Garcia, D.J. (Daniel J.); Carretero, J. (Julian); Peinado, P. (Paola)Mammalian SWI/SNF (SWitch/Sucrose Non-Fermentable) complexes are ATP-dependent chromatin remodelers whose subunits have emerged among the most frequently mutated genes in cancer. Studying SWI/SNF function in cancer cell line models has unveiled vulnerabilities in SWI/SNF-mutant tumors that can lead to the discovery of new therapeutic drugs. However, choosing an appropriate cancer cell line model for SWI/SNF functional studies can be challenging because SWI/SNF subunits are frequently altered in cancer by various mechanisms, including genetic alterations and post-transcriptional mechanisms. In this work, we combined genomic, transcriptomic, and proteomic approaches to study the mutational status and the expression levels of the SWI/SNF subunits in a panel of 38 lung adenocarcinoma (LUAD) cell lines. We found that the SWI/SNF complex was mutated in more than 76% of our LUAD cell lines and there was a high variability in the expression of the different SWI/SNF subunits. These results underline the importance of the SWI/SNF complex as a tumor suppressor in LUAD and the difficulties in defining altered and unaltered cell models for the SWI/SNF complex. These findings will assist researchers in choosing the most suitable cellular models for their studies of SWI/SNF to bring all of its potential to the development of novel therapeutic applications.
- Exosomes in liquid biopsy: the nanometric world in the pursuit of precision oncology(2021) Montuenga-Badia, L.M. (Luis M.); Valencia, K. (Karmele)Among the different components that can be analyzed in liquid biopsy, the utility of exosomes is particularly promising because of their presence in all biological fluids and their potential for multicomponent analyses. Exosomes are extracellular vesicles with an average size of similar to 100 nm in diameter with an endosomal origin. All eukaryotic cells release exosomes as part of their active physiology. In an oncologic patient, up to 10% of all the circulating exosomes are estimated to be tumor-derived exosomes. Exosome content mirrors the features of its cell of origin in terms of DNA, RNA, lipids, metabolites, and cytosolic/cell-surface proteins. Due to their multifactorial content, exosomes constitute a unique tool to capture the complexity and enormous heterogeneity of cancer in a longitudinal manner. Due to molecular features such as high nucleic acid concentrations and elevated coverage of genomic driver gene sequences, exosomes will probably become the "gold standard" liquid biopsy analyte in the near future.
- Protein biomarkers in lung cancer screening: technical considerations and feasibility assessment(Elsevier, 2024) Seijo, L. (Luis); Calle-Arroyo, C. (Carlos) de la; Pineda-Lucena, A. (Antonio); Detterbeck, F. (Frank); Bernasconi-Bisio, F. (Franco); Johansson, M. (Mattias); Montuenga-Badia, L.M. (Luis M.); Orive-Mauleón, D. (Daniel); Hung, J.R. (Rayjean); Valencia, K. (Karmele); Echepare, M. (Mirari); Robbins, H.A. (Hilary); Fernandez-Sanmamed, M. (Miguel)Lung cancer remains the leading cause of cancer-related deaths worldwide, mainly due to late diagnosis and the presence of metastases. Several countries around the world have adopted nation-wide LDCT-based lung cancer screening that will benefit patients, shifting the stage at diagnosis to earlier stages with more therapeutic options. Biomarkers can help to optimize the screening process, as well as refine the TNM stratification of lung cancer patients, providing information regarding prognostics and recommending management strategies. Moreover, novel adjuvant strategies will clearly benefit from previous knowledge of the potential aggressiveness and biological traits of a given early-stage surgically resected tumor. This review focuses on proteins as promising biomarkers in the context of lung cancer screening. Despite great efforts, there are still no successful examples of biomarkers in lung cancer that have reached the clinics to be used in early detection and early management. Thus, the field of biomarkers in early lung cancer remains an evident unmet need. A more specific objective of this review is to present an up-to-date technical assessment of the potential use of protein biomarkers in early lung cancer detection and management. We provide an overview regarding the benefits, challenges, pitfalls and constraints in the development process of protein-based biomarkers. Additionally, we examine how a number of emerging protein analytical technologies may contribute to the optimization of novel robust biomarkers for screening and effective management of lung cancer.
- Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene(Nature Publishing Group, 2004) Pio, R. (Rubén); Medina, P.P. (Pedro P.); Carretero, J. (J.); Montuenga-Badia, L.M. (Luis M.); Sanchez-Cespedes, M. (Montserrat)Germline mutations of the LKB1 gene are responsible for Peutz-Jeghers syndrome (PJS), an autosomal dominant inherited disorder bestowing an increased risk of cancer. We have recently demonstrated that LKB1 inactivating mutations are not confined to PJS, but also appear in lung adenocarcinomas of sporadic origin, including primary tumors and lung cancer cell lines. To accurately determine the frequency of inactivating LKB1 gene mutations in lung tumors we have sequenced the complete coding region of LKB1 in 21 additional lung cancer cell lines. Here we describe the mutational status of LKB1 gene in 30 lung cancer cell lines from different histopathological types, including 11 lung adenocarcinomas (LADs) and 11 small cell lung cancers (SCLCs). LKB1 gene alterations were present in six (54%) of the LAD cell lines tested but in none of the other histological types. Similar to our previous observations in primary tumors, all point mutations were of the nonsense or frameshift type, leading to an abnormal, truncated protein. Moreover, 2 cell lines (A427 and H2126) harbored large gene deletions that spanned several exons. Hence, we have identified additional lung cancer cell lines carrying inactivating mutations of the LKB1 tumor suppressor gene, further attesting to the significance of this gene in the development of LADs and providing new natural LKB1 knockouts for studies of the biological function of the LKB1 protein.
- The role of adrenomedullin as a growth regulatory peptide in the normal and malignant setting(American Society of Animal Science, 1999) Miller, M.J. (Mae Jean); Pio, R. (Rubén); Walsh, T. (Thomas); Garayoa, M. (Mercedes); Montuenga-Badia, L.M. (Luis M.); Cuttitta, F. (Frank); Martinez, A. (Alfredo)Adrenomedullin (AM ) is a recently discovered pluripo1ent peptide initially isolated fraro a human adrenal gland tumor (pheochromocytoma). Adrenomedullin has been shown to have an ancient origin with immunoreactive species fOWld in maromals, birds, reptiles, amphibians, fish , and eemnoderms (s t a r fish ). Given its highly conserved evolutionary expression, AM is thought te playa critica! !•ole in spedes survival. This peptide has been show lo mediate a variety of physiological fu netlons, of which iis involvement in growth r egulation wil1 be tbe central focus of this papero In the following text, we will review the cited Iiterature in this area and inelude our own observations regarding AM express10n in carcinogenesis, embryogenesis, and wound r epair. Adrenomedullin will be shown to induce both growth promotian or growth suppression depending on the taTget cell examined aud the sUITounding nutritional environment in which the analysis was done. Its implied role as a mitogen, aogiogenic fador, and apoplosis survival factor will be critiqued and evaluated relative to its impor tance in the cel! proHferation process. Finally, we will review the a ntimicrobiaJ effect AM has on severa1 human pathogens ( Es•cherichia coli and Candidn albi.cans) and demonstrate its partieipation in the host immune response syslem as a first line defense peptide.