Targeted Cancer Proteomics Laboratory

Josep Villanueva obtained his Ph.D. in Biochemistry and Molecular Biology in 2000 from the Autonomous University of Barcelona.

In 2002, he accepted a postdoctoral fellowship in the laboratory of Dr. Paul Tempst at Memorial Sloan-Kettering Cancer Center (New York, USA). There, he participated in a new clinical proteomics program whose objective was the identification of serum cancer biomarkers. He became the lead-scientist in the development of a unique automated platform for the measurement of peptides in serum using magnetic beads and a mass spectrometry read-out.
Following the ‘technology phase’, he collaborated with clinicians and clinical chemists at MSKCC effectively demonstrating that a limited subset of serum peptides provides accurate class discrimination between patients with three types of solid tumors and healthy controls.  Sequence analysis revealed that these peptides were generated by ‘cancer-type’-specific exopeptidase activities.

In 2006, he was promoted to senior staff scientist at MSKCC. Intent on becoming an independent investigator, he started developing a longer-term project exploring targeted approaches to tumor biomarker discovery. Since then, he has developed a new methodology for the high-throughput proteomics profiling of cell-secreted inventories (the ‘secretome’) with a clear focus on biomarkers. The first fruit of this new phase in his career was his first publication as senior author in 2009.

His postdoctoral work is widely respected and recognized in the proteomics biomarker discovery field. He is the first author on all ten Clinical Proteomic publications from the Tempst laboratory. Furthermore, the platform developed by Dr. Villanueva has been licensed to a biotech company – this is currently available as a commercial solution for proteomic biomarker discovery. He also serves in the Editorial Board of the Journal of Proteomics.
In 2009, Dr. Villanueva returned to Barcelona as an independent researcher and became the group leader of the Targeted Cancer Proteomics laboratory at VHIO. His research program is aimed at the discovery of tumor-specific biomarkers and therapeutic targets using proteomic methodologies to improve cancer diagnostics and therapeutic treatment. 

jvillanueva@vhio.net

 

PRINCIPAL INVESTIGATOR

RESEARCH LINES

Tumor cell communication with its microenvironment plays a key role in tumor initiation and progression. Tumor cells hijack the tumor microenvironment ecosystem via paracrine signaling to promote a pro-oncogenic microenvironment that is critical for the establishment of primary and metastatic tumors.
The working hypothesis of the laboratory is that cellular signaling pathways are altered during the tumorigenesis process, and that these alterations are translated into differential protein secretion, which potentially can be exploited to discover secreted markers. Furthermore, some of the differentially regulated proteins could be direct extracellular messengers of intracellular signaling pathways contributing to key steps in cancer initiation and progression, therefore becoming potential therapeutic targets. Therefore, the aim of the laboratory is to discover secreted tumor-specific biomarkers and therapeutic targets to improve cancer diagnostics and therapeutic treatment.
Proteomic technologies offer the advantage of a genome-scale search for tumor-specific biomarkers and drug targets and could revolutionize early detection and molecular characterization of cancer through non-invasive methods. However, the field of cancer proteomics has encountered problems with reproducibility and limitations related to the massive complexity of biological samples. Consequently, the laboratory will focus on the discovery of biomarkers and drug targets using the proteomic profiling of sub-proteomes, rather than whole tissues or plasma/serum. By using a new proteomics approach capable of the quantitative profiling of the secreted sub-proteome (‘secretome’) of cells, we will generate secretome signatures in different breast cancer model systems, particularly from the primary culture of tumors. The secretome signatures will then be analyzed using differential expression statistics and put in the context of intracellular signaling transduction using pathway analysis software.
Large-scale cancer genome studies have recently shown that tumors have several mutations that differ not only among cancer types, but also from patient to patient. Most of the mutations affect a relatively small number of pathways. Accordingly, the laboratory will take an innovative approach towards biomarker discovery in which tumor-specific pathways rather than individual proteins are targeted. Once the perturbed pathways are identified in secretome signatures, it will be easier to monitor different aspects of cancer progression and therapy by focusing on pathways instead of individual genes. We are confident that the discovery of secreted tumor-specific, pathway-based biomarkers will play a key role in the fight against cancer.

SELECTED PUBLICATIONS

Villanueva J, Nazarian A, Lawlor K, Tempst P. Monitoring peptidase activities in complex proteomes by MALDI-TOF mass spectrometry. Nature Protocols 2009, 4:1167-83.

Lawlor K, Nazarian A, Lacomis L, Tempst P, Villanueva J. Pathway-Based Biomarker Search by High-Throughput Proteomics Profiling of Secretomes. Journal of Proteome Research. 2009, 8 (3), 1489-1503.

Villanueva J, Nazarian A, Lawlor K, Yi SS, Robbins RJ, Tempst P A Sequence-specific Exopeptidase Activity Test (SSEAT) for “Functional” Biomarker Discovery. Molecular & Cellular Proteomics. 2008, 7:509-18.

Villanueva J, Philip J, DeNoyer L, Tempst P. Data analysis of assorted serum peptidome profiles. Nature Protocols 2007, 2:588-602.

Villanueva J, Lawlor K, Toledo-Crow R, Tempst P. Automated serum peptide profiling. Nature Protocols. 2006, 1:880–891.

Villanueva J, Martorella AJ, Lawlor K, Philip J, Fleisher M, Robbins RJ, Tempst P. Serum peptidome patterns that distinguish metastatic thyroid carcinoma from cancer-free controls are unbiased by gender and age. Molecular & Cellular Proteomics. 2006, 5:1840-52.

Villanueva J, Shaffer DR, Philip J, Chaparro CA, Erdjument-Bromage H, Olshen AB, Fleisher M, Lilja M, Brogi E, Boyd J, Sanchez-Carbayo M, Holland EC, Cordon-Cardo C, Scher HI, and Tempst P. Differential Exoprotease Activities Confer Tumor-Specific Serum ‘Peptidome’ Patterns. Journal of Clinical Investigation 2006,116:271-284.

Villanueva J, Martorella AJ, Lawlor K, Philip J, Fleisher M, Robbins RJ, Tempst P. Serum peptidome patterns that distinguish metastatic thyroid carcinoma from cancer-free controls are unbiased by gender and age. Molecular & Cellular Proteomics. 2006, 5:1840-52.

 

 

RESEARCH PROJECTS

Funding Agency: ISCIII (Miguel Servet)
Title: “Quantitative Proteomic Profiling of Secretomes for Drug Target Discovery”
PI: Josep Villanueva
Duration: 2009-2011

Funding Agency: ISCIII (FIS)
Title: “Pathway Based Secretomes in Breast Cancer Biomarker Discovery”
PI: Josep Villanueva
Duration: 2010-2012

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