VHIO's Cancer Genomics, Molecular Oncology, and Proteomics, led by Ana Vivancos, Paolo Nuciforo, and Francesc Canals respectively, are responsible for the development of VHIO's cutting-edge core technologies and platforms. These groups also pursue, implement and develop their own independent research lines and projects.
Francesco M. Mancuso
Bioinformatics Technical Auxiliary
Deborah G. Lo Giacco
VHIO's Cancer Genomics Group serves as a Core Technology laboratory. In addition, we are dedicated to translational research as well as novel genomic test development.
We provide cutting-edge applications in cancer genomics through state-of-the-art technologies and the development of novel, fully validated tests that are used in the clinical research setting (Prescreening Program). Our lab is equipped with an n-Counter (Nanostring) platform, two digital PCR platforms (BEAMing Sysmex and ddPCR, BIO-RAD) and two NextGen Sequencers; MiSeq and HiSeq2500, Illumina.
VHIO's Prescreening Program is nucleated around the activity of two VHIO groups - our Cancer Genomics Group and Molecular Oncology led by Paulo Nuciforo, and centers on performing molecular profiling in over 1500 patients each year as potential candidates for enrollment in our Phase I clinical trials led by VHIO's Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa”, directed by Elena Garralda (click here).
Patients' suitability for inclusion in any given clinical trial is assessed based on their respective genomic or pathologic profile. Our Group has developed and routinely implemented several tests for our Prescreening Program. Two are based on NGS: an Amplicon-seq approach to sequence 67 genes (Illumina), as well as a 400-gene capture panel. Another two are based on nCounter (Nanostring): a gene fusion panel (with the capacity of detecting over 100 recurrent gene fusions) and a Copy Number Alteration panel (detecting 59 genes). As a reflection of our dedication to excellence and quality in the services we provide, we have achieved ISO 15189 accreditation for our Amplicon-seq testing method.
Our research activities focus on developing novel multiplexed tests that are optimized to FFPE-derived nucleic acids. Once developed, they are validated and used in clinical and translational research.
We are involved in a number of translational research projects including the identification of mechanisms of resistance to targeted therapies, with particular emphasis on liquid biopsy, specifically ctDNA as well as tumor educated platelets (TEPs).
Figure: A.- Digital PCR arises 500 times superior sensitivity compared to Next Generation Sequencing (NGS). This improvement in technology allows detection of mutations in circulating tumor DNA from plasma samples, a revolutionary technic known as liquid biopsy. B.-The amount of cell free DNA (cfDNA) in plasma is minimum but varies greatly depending on the tumor type (CRC, colorectal cancer; NSCLC, non-small cell lung cancer; GIST, gastrointestinal stroma tumors). C.- NSCLC patient follow up of tumor evolution along treatments. Measurement of EGFR sensitizing L858R and resistance T790M mutant allele frequencies (MAFs) in plasma, both increase during second generation anti-EGFR treatment (erlotinib) and are detectable 6 months prior to standard CT-Scan progression disease (PD) diagnosis; upon initiation of anti-EGFR third generation treatment (osimertinib), MAFs substantially diminish revealing a good response to treatment. Finally, total cfDNA increases upon PD, and decreases upon effectiveness of osimertinib treatment.
Martinez-Marti A, Felip E, Matito J, Mereu E, Navarro A, Cedrés S, Pardo N, Martinez de Castro A, Remon J, Miquel J M, Guillaumet-Adkins A, Nadal E, Rodriguez-Esteban G, Arqués O, Fasani R, Nuciforo P, Heyn H, Villanueva A, Palmer H G, Vivancos A. Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC). Ann Oncol. 2017 Oct 1;28(10):2451-2457.
García-Foncillas J, Alba E, Aranda E, Díaz-Rubio E, López-López R, Tabernero J, Vivancos A. Incorporating BEAMing technology as a liquid biopsy into clinical practice for the management of colorectal cancer patients: an expert taskforce review. Ann Oncol. 2017 Dec 1;28(12):2943-2949.
Dienstmann R, Elez E, Argiles G, Matos I, Sanz-Garcia E, Ortiz C, Macarulla T, Capdevila J, Alsina M, Sauri T, Verdaguer H, Vilaro M, Ruiz-Pace F, Viaplana C, Garcia A, Landolfi S, Palmer HG, Nuciforo P, Rodon J, Vivancos A, Tabernero J. Analysis of mutant allele fractions in driver genes in colorectal cancer - biological and clinical insights. Mol Oncol. 2017 Sep;11(9):1263-1272.
Grasselli J, Elez E, Caratù G, Matito J, Santos C, Macarulla T, Vidal J, Garcia M, Viéitez JM, Paéz D, Falcó E, Lopez Lopez C, Aranda E, Jones F, Sikri V, Nuciforo P, Fasani R, Tabernero J, Montagut C, Azuara D, Dienstmann R, Salazar R, Vivancos A. Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer. Ann Oncol. 2017 Jun 1;28(6):1294-1301.
Mª Ángeles Díaz
Mª del Carmen Díaz
The mission of VHIO's Molecular Oncology Group is to apply state-of-the-art tissue-based technologies to basic, translational, and clinical research with a clear focus on the development and validation of novel tumor biomarkers for precision medicine against cancer. Our group also serves as one of VHIO's Core Technology Platforms and is therefore central to research performed at our Institute.
We actively participate in all research projects involving the use of human tissue collected from patients, including biomarker analyses for patient stratification and inclusion in clinical trials, tissue banking and the development of primary xenograft models.
Activities as a Core Facility in 2017: We provided support for approximately 250 clinical trials conducted at Vall d'Hebron, representing approx. 70% of all trials open at our institution. Our involvement in clinical trials ranges from the coordination of sample collection, storage and shipment, developing and running multiple assays for real-time patient inclusion, as well as pharmacodynamic monitoring and dose finding.
In 2017, we have performed more than 4000 molecular determinations on samples for patient inclusion in clinical trials and over 24,000 tests to support basic and translation research programs. We have also been the central laboratory of choice for 10 international studies, and successfully maintained the prestigious ISO15189 quality accreditation. Additionally, we have achieved the flexible scope and expansion of the catalogue of molecular tests run under accreditation.
Group research activities in 2017: We developed a predictive model based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-posiive breast cancer treated with chemo-free dual HER2 blockade (Nuciforo et al. Ann Oncol. 2017). We have also collaborated in developing recommendations on assessing TILs in different types of solid tumors (Hendry et al. Adv Anat Pathol. 2017) and in identifying an adaptive immune response gene signature predictive of clinical outcome after PD-1 blockade (Prat et al. Cancer Res. 2017).
We have explored the importance of microbiota in colorectal cancer development. By developing an in situ hybridization mRNA assay, we evidenced Fusobacterium nucleatum persistence in liver metastases of colorectal cancer patients and antibiotic response in patient-derived tumor models (Bullman et al. Science. 2017) – see Figure.
Results of the first-in-human phase I study of oral S49076, a MET/AXL/FGFR inhibitor, in advanced solid tumors were also published together with the associated pharmacodynamics readouts generated in our laboratory (Rodon et al. Eur J Cancer. 2017).
Lastly, our group is currently working on developing a multiplex in situ technology to enable a complete set of diagnostic and research immunohistochemistry and in situ hybridization markers on a single tissue slide.
Figure: Fusobacterium nucleatum (FN) in colorectal cancer - 1 red dot = 1 bacteria RNA molecule
Bullman S, Pedamallu CS, Sicinska E, Clancy TE, Zhang X, Cai D, Neuberg D, Huang K, Guevara F, Nelson T, Chipashvili O, Hagan T, Walker M, Ramachandran A, Diosdado B, Serna G, Mulet N, Landolfi S, Ramon Y Cajal S, Fasani R, Aguirre AJ, Ng K, Élez E, Ogino S, Tabernero J, Fuchs CS, Hahn WC, Nuciforo P, Meyerson M. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science 2017 Dec 15;358(6369):1443-1448. doi: 10.1126/science.aal5240. Epub 2017 Nov 23.
Nuciforo P, Pascual T, Cortés J, Llombart-Cussac A, Fasani R, Paré L, Oliveira M, Galvan P, Martínez N, Bermejo B, Vidal M, Pernas S, López R, Muñoz M, Garau I, Manso L, Alarcón J, Martínez E, Rodrik-Outmezguine V, Brase JC, Villagrasa P, Prat A, Holgado E. A predictive model of pathological response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade. Ann Oncol. 2017 Oct 12. doi: 10.1093/annonc/mdx647. [Epub ahead of print].
Zabala-Letona A, Arruabarrena-Aristorena A, Martín-Martín N, Fernandez-Ruiz S, Sutherland JD, Clasquin M, Tomas-Cortazar J, Jimenez J, Torres I, Quang P, Ximenez-Embun P, Bago R, Ugalde-Olano A, Loizaga-Iriarte A, Lacasa-Viscasillas I, Unda M, Torrano V, Cabrera D, van Liempd SM, Cendon Y, Castro E, Murray S, Revandkar A, Alimonti A, Zhang Y, Barnett A, Lein G, Pirman D, Cortazar A, Arreal L, Prudkin L, Astobiza I, Valcarcel-Jimenez L, Zuñiga-García P, Fernandez-Dominguez I, Piva M, Caro-Maldonado A, Sánchez-Mosquera P, Castillo-Martín M, Serra V, Beraza N, Gentilella A, Thomas G, Azkargorta M, Elortza F, Farràs R, Olmos D, Efeyan A, Anguita J, Muñoz J, Falcón-Pérez JM, Barrio R, Macarulla T, Mato JM, Martinez-Chantar ML, Cordon-Cardo C, Aransay AM, Marks K, Baselga J, Tabernero J, Nuciforo P, Manning BD, Marjon K, Carracedo A. MTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature. 2017 Jul 6;547(7661):109-113.
Llombart-Cussac A, Cortes J, Paré L, Galvan P, Bermejo B, Martínez N, Vidal M, Pernas S, López R, Muñoz M, Nuciforo P, Morales S, Oliveira M, de la Peña L, Peláez A, Prat A. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol. 2017 Apr;18(4):545-554. doi: 10.1016/S1470-2045(17)30021-9. Epub 2017 Feb 24.
Proteomics involves the characterization of the entire set of proteins - proteome - expressed by a particular cell or tissue under specific physiological or pathological conditions. The application of proteomic technologies to cancer research is a rapidly expanding field - not only for basic research but also for the discovery of diagnostic or disease-progression biomarkers. We mainly focus on applying proteomic techniques to the identification and characterization of substrates of metalloproteases involved in tumor progression.
Metalloproteases of the ADAM and ADAMTS families play a crucial role in the regulation of the tumor microenvironment by mediating the remodeling of the extracellular matrix and the cleavage of specific extracellular and membrane proteins. Insights into the substrates of these proteases in the context of tumor cells are required in order to elucidate their role in tumor growth and metastasis as well as evaluate their potential as therapeutic targets.
Our group employs mass spectrometry-based proteomic strategies to search for new substrates of these proteases and analyze their involvement in tumor progression.
We also adopt proteomic techniques for the screening and validation of biomarkers for cancer diagnostics, precision therapy against cancer, and the tracking of disease. Our focus centers on the development of mass spectrometry-based assays for the analysis of biomarkers in clinical samples. VHIO's Proteomics Group is a member of the Spanish Consortium Chromosome 16 HPP which forms part of the HUPO Human Proteome Project. Following a chromosome-centric strategy, this multicenter and international project aims at developing an entire map of the proteins encoded by the human genome to advance our understanding of human biology in health and disease.
As a Core Facility, we provide state-of-the-art proteomic methodologies to VHIO researchers as well as implement new developments within the field to offer the very latest proteomic strategies and technologies.
Figure: Proteomic characterization of colorectal patient-derived xenograph (PDX) models. Proteomic and phosphoproteomic analysis of patient-derived mouse model tumors allows the molecular characterization of tumor subtypes. Colorectal tumors of MSS and MSI subtypes can be correctly classified on the basis of tumor derived proteins, phosphorylated proteins involved in signaling, or microenvironment proteins, of mouse origin in the PDX model.
García-Berrocoso T, Llombart V, Colàs-Campàs L, Hainard A, Licker V, Penalba A, Ramiro L, Simats A, Bustamante A, Martínez-Saez E, Canals F, Sanchez JC, Montaner J. Single Cell Immuno-laser Microdissection Coupled to Label-free Proteomics to Reveal the Proteotypes of Human Brain Cells After Ischemia. Mol Cell Proteomics. 2017 Nov 13. [Epub ahead of print]
Mateo F, Arenas EJ, Aguilar H, Serra-Musach J, de Garibay GR, Boni J, Maicas M, Du S, Iorio F, Herranz-Ors C, Islam A, Prado X, Llorente A, Petit A, Vidal A, Català I, Soler T, Venturas G, Rojo-Sebastian A, Serra H, Cuadras D, Blanco I, Lozano J, Canals F, Sieuwerts AM, de Weerd V, Look MP, Puertas S, García N, Perkins AS, Bonifaci N, Skowron M, Gómez-Baldó L, Hernández V, Martínez-Aranda A, Martínez-Iniesta M, Serrat X, Cerón J, Brunet J, Barretina MP, Gil M, Falo C, Fernández A, Morilla I, Pernas S, Plà MJ, Andreu X, Seguí MA, Ballester R, Castellà E, Nellist M, Morales S, Valls J, Velasco A, Matias-Guiu X, Figueras A, Sánchez-Mut JV, Sánchez-Céspedes M, Cordero A, Gómez-Miragaya J, Palomero L, Gómez A, Gajewski TF, Cohen EE, Jesiotr M, Bodnar L, Quintela-Fandino M, López-Bigas N, Valdés-Mas R, Puente XS, Viñals F, Casanovas O, Graupera M, Hernández-Losa J, Ramón Y Cajal S, García-Alonso L, Saez-Rodriguez J, Esteller M, Sierra A, Martín-Martín N, Matheu A, Carracedo A, González-Suárez E, Nanjundan M, Cortés J, Lázaro C, Odero MD, Martens JW, Moreno-Bueno G, Barcellos-Hoff MH, Villanueva A, Gomis RR, Pujana MA. Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition. Oncogene. 2017. May 11;36(19):2737-2749
Vialas V, Colomé-Calls N, Abian J, Aloria K, Alvarez-Llamas G, Antúnez O, Arizmendi JM, Azkargorta M, Barceló-Batllori S, Barderas MG, Blanco F, Casal JI, Casas V, de la Torre C, Chicano-Gálvez E, Elortza F, Espadas G, Estanyol JM, Fernandez-Irigoyen J, Fernandez-Puente P, Fidalgo MJ, Fuentes M, Gay M, Gil C, Hainard A, Hernaez ML, Ibarrola N, Kopylov AT, Lario A, Lopez JA, López-Lucendo M, Marcilla M, Marina-Ramírez A, Marko-Varga G, Martín L, Mora MI, Morato-López E, Muñoz J, Odena MA, de Oliveira E, Orera I, Ortea I, Pasquarello C, Ray KB, Rezeli M, Ruppen I, Sabidó E, Del Pino MM, Sancho J, Santamaría E, Vazquez J, Vilaseca M, Vivanco F, Walters JJ, Zgoda VG, Corrales FJ, Canals F, Paradela A. A multicentric study to evaluate the use of relative retention times in targeted proteomics. J Proteomics. 2017 Jan 30;152:138-149.
Llombart V, Trejo SA, Bronsoms S, Morancho A, Feifei M, Faura J, García-Berrocoso T, Simats A, Rosell A, Canals F, Hernández-Guillamón M, Montaner J. Profiling and identification of new proteins involved in brain ischemia using MALDI-imaging-mass-spectrometry. J Proteomics. 2017Jan 30;152:243-253.