TUMOR BIOMARKERS GROUP

PRECLINICAL & TRANSLATIONAL RESEARCH
Tumor Biomarkers Group

JOSEP VILLANUEVA
Principal Investigator
Biosketch

Tumor cell communication with its microenvironment plays an important role in tumor initiation and progression. Cancer cells hijack the tumor microenvironment ecosystem via paracrine signaling to promote a pro-oncogenic microenvironment that is crucial for the development of primary and metastatic tumors.

Our main aim is to characterize the mechanisms adopted by these cells to communicate amongst themselves as well as with their microenvironment during tumorigenesis. We aim to exploit these data to advance biomarker and drug target discovery.

Our team’s working hypothesis is that cellular signaling pathways undergo alterations during the tumorigenesis process and that these changes are translated into differential protein secretion, which can also potentially be used to identify secreted markers. Furthermore, some of the differentially regulated proteins could be direct extracellular messengers of intracellular signaling pathways contributing to fundamental stages implicated in cancer initiation and progression, therefore representing potential therapeutic targets.

The methodological focus of our group centers on profiling the secreted sub-proteome (‘secretome’) of cells by quantitative mass spectrometry. Most secreted proteins contain a signal peptide that directs their sorting to the extracellular space through the endoplasmic reticulum (ER)–Golgi secretory pathway. One of the most striking observations when secretome profiles are carefully produced and analyzed is that they contain hundreds of theoretical intracellular proteins.

Recent reports showing intracellular proteins with alternative extracellular functions suggest that new protein functions associated with alternative subcellular localizations could implicated in tumorigenesis. In line with this notion, our recent efforts within the context of therapeutics and tumor invasion have led us to hypothesize that the characterization of non-classical protein secretion could lead to the development of novel anti-cancer therapies.

STRATEGIC GOALS

  • Exploit the role of non-classical secretion linked to tumor invasion and metastasis to identify biomarkers and therapeutic targets against breast cancer.
  • Characterize the role of extracellular HMGA1 in breast cancer invasion and metastasis.
  • The characterization of mechanisms adopted by tumor cells to communicate with their microenvironment during treatment to establish secreted response/resistance biomarkers to cancer drug therapies.

HIGHLIGHTS

  • We have recently generated monoclonal antibodies (mAbs) against HMGA1 and now validating them in vitro. The results obtained using the antibodies in migration, invasion and cancer signaling assays are very promising. We foresee to continue validating them as biomarkers predicting metastasis in breast cancer, and as drugs that could block invasion and metastasis in Triple-Negative Breast Cancer (TNBC).

 


TEAM

  • Principal Investigator
    • Josep Villanueva
  • Post-doctoral Fellows
    • Chiara Bellio
    • Olga Méndez
    • Nathalie Meo-Evoli
  • Graduate Student
    • Mireia Pujals
  •  Technicians
    • Mireia Pares
    • Candida Salvans
    • Gabriel Tamayo

 


Most relevant scientific publications

  • Méndez O, Pérez J, Soberino J, Racca F, Cortés J, Villanueva J. Clinical Implications of Extracellular HMGA1 in Breast Cancer. Int J Mol Sci. 2019. 20(23), 5950.
  • Méndez O, Peg V, Salvans C, Pujals M, Fernández Y, Abasolo I, Pérez J, Matres  A, Valeri M, Gregori J, Villarreal L, Schwartz S Jr, Ramon Y Cajal S, Tabernero J, Cortés J, Arribas J, Villanueva J. Extracellular HMGA1 Promotes Tumor Invasion and Metastasis in Triple-Negative Breast Cancer. Clin Cancer Res. 2018 Dec 15;24(24):6367-6382
  • Méndez O, Villanueva J. Challenges and opportunities for cell line secretomes in cancer proteomics.Proteomics Clin Appl. 2015;9(3-4):348-357.
  • Katsila T, Juliachs M, Gregori J, Macarulla T, Villarreal L, Bardelli A, Torrance C, Elez E, Tabernero J, Villanueva J. Circulating pEGFR is a candidate response biomarker of cetuximab therapy in colorectal cancer. Clin. Cancer Res. 2014 Dec; 20(24): 6346-56
  • Villarreal L, Méndez O, Salvans C, Gregori J, Baselga J, Villanueva J*. Unconventionalsecretion is a major contributor of cancer cell line secretomes. Mol Cell Proteomics. 2013, 12(5):1046-60.
  • Gregori J, Méndez O, Katsila T, Pujals M, Salvans C, Villarreal L, Arribas J, Tabernero J, Sánchez A, Villanueva J. Enhancing the Biological Relevance of Secretome-Based Proteomics by Linking Tumor Cell Proliferation and Protein Secretion. J. Proteome Res. 2014 Jul;
  • Gregori J, Villarreal L, Sánchez A, Baselga J, Villanueva J. An effect size filter improves the reproducibility in spectral counting-based comparative proteomics. J Proteomics 2013 Dec; 95: 55-65
  • Gregori J, Villarreal L, Méndez O, Sánchez A, Baselga J, Villanueva J. Batch effects correction improves the sensitivity of significance tests in spectral counting-based comparative discovery proteomics. J Proteomics 2012 Jul; 75(13): 3938-51
  • Lawlor K, Nazarian A, Lacomis L, Tempst P, Villanueva J*. Pathway-based biomarker search by high-throughput proteomics profiling of secretomes. J Proteome Research. 2009. 8(3):1489-503.

All publications

  • Méndez O, Pérez J, Soberino J, Racca F, Cortés J,  Villanueva J. Clinical Implications of Extracellular HMGA1 in Breast Cancer. Int J Mol Sci. 2019, 20(23), 5950.
  • Arreal L, Piva M, Fernández S, Revandkar A, Schaub-Clerigué A, Villanueva J, Zabala-Letona A, Pujana M, Astobiza I, Cortazar AR, Hermanova I, Bozal-Basterra L, Arruabarrena-Aristorena A, Crespo JR, Valcarcel-Jimenez L, Zúñiga-García P, Canals F, Torrano V, Barrio R, Sutherland JD, Alimonti A, Martin-Martin N, Carracedo A.Targeting PML in triple negative breast cancer elicits growth suppression and senescence. Cell Death Differ. 2019 Oct 1. doi: 10.1038/s41418-019-0407-5.
  • Méndez O, Peg V, Salvans C, Pujals M, Fernández Y, Abasolo I, Pérez J, Matres  A, Valeri M, Gregori J, Villarreal L, Schwartz S Jr, Ramon Y Cajal S, Tabernero J, Cortés J, Arribas J, Villanueva J. Extracellular HMGA1 Promotes Tumor Invasion and Metastasis in Triple-Negative Breast Cancer. Clin Cancer Res. 2018 Dec 15;24(24):6367-6382
  • Zacarias-Fluck MF, Morancho B, Vicario R, Luque Garcia A, Escorihuela M, Villanueva J, Rubio IT, Arribas J.  Effect of cellular senescence on the growth of HER2-positive breast cancers. J. Natl. Cancer Inst. 2015 May; 107(5)
  • Morancho B, Martínez-Barriocanal Á, Villanueva J, Arribas J.  Role of ADAM17 in the non-cell autonomous effects of oncogene-induced senescence. Breast Cancer Res. 2015; 17: 106
  • Katsila T, Juliachs M, Gregori J, Macarulla T, Villarreal L, Bardelli A, Torrance C, Elez E, Tabernero J, Villanueva J.  Circulating pEGFR is a candidate response biomarker of cetuximab therapy in colorectal cancer. Clin. Cancer Res. 2014 Dec; 20(24): 6346-56
  • Nazarian A, Lawlor K, Yi SS, Philip J, Ghosh M, Yaneva M, Villanueva J, Saghatelian A, Assel M, Vickers AJ, Eastham JA, Scher HI, Carver BS, Lilja H, Tempst P.  Inhibition of circulating dipeptidyl peptidase 4 activity in patients with metastatic prostate cancer. Mol. Cell Proteomics 2014 Nov; 13(11): 3082-96
  • Gregori J, Méndez O, Katsila T, Pujals M, Salvans C, Villarreal L, Arribas J, Tabernero J, Sánchez A, Villanueva J.  Enhancing the Biological Relevance of Secretome-Based Proteomics by Linking Tumor Cell Proliferation and Protein Secretion. J. Proteome Res. 2014 Jul;
  • Segura V, Medina-Aunon JA, Mora MI, Martínez-Bartolomé S, Abian J, Aloria K, Antúnez O, Arizmendi JM, Azkargorta M, Barceló-Batllori S, Beaskoetxea J, Bech-Serra JJ, Blanco F, Monteiro MB, Cáceres D, Canals F, Carrascal M, Casal JI, Clemente F, Colomé N, Dasilva N, Díaz P, Elortza F, Fernández-Puente P, Fuentes M, Gallardo O, Gharbi SI, Gil C, González-Tejedo C, Hernáez ML, Lombardía M, Lopez-Lucendo M, Marcilla M, Mato JM, Mendes M, Oliveira E, Orera I, Pascual-Montano A, Prieto G, Ruiz-Romero C, Sánchez del Pino MM, Tabas-Madrid D, Valero ML, Vialas V, Villanueva J, Albar JP, Corrales FJ.  Surfing transcriptomic landscapes. A step beyond the annotation of chromosome 16 proteome. J. Proteome Res. 2014 Jan; 13(1): 158-72
  • Gregori J, Villarreal L, Sánchez A, Baselga J, Villanueva J.  An effect size filter improves the reproducibility in spectral counting-based comparative proteomics. J Proteomics 2013 Dec; 95: 55-65
  • Angelini PD, Zacarias Fluck MF, Pedersen K, Parra-Palau JL, Guiu M, Bernadó Morales C, Vicario R, Luque-García A, Navalpotro NP, Giralt J, Canals F, Gomis RR, Tabernero J, Baselga J, Villanueva J, Arribas J.  Constitutive HER2 signaling promotes breast cancer metastasis through cellular senescence.Cancer Res. 2013 Jan; 73(1): 450-8
  • Gregori J, Villarreal L, Méndez O, Sánchez A, Baselga J, Villanueva J.  Batch effects correction improves the sensitivity of significance tests in spectral counting-based comparative discovery proteomics. J Proteomics 2012 Jul; 75(13): 3938-51
  • Sánchez A, Villanueva J.  PI3K-based molecular signatures link high PI3K pathway activity with low ER levels in ER+ breast cancer. Expert Rev Proteomics 2010 Dec; 7(6): 819-21
  • Villanueva J, Nazarian A, Lawlor K, Tempst P.  Monitoring peptidase activities in complex proteomes by MALDI-TOF mass spectrometry. Nat Protoc 2009; 4(8): 1167-83
  • Lawlor K, Nazarian A, Lacomis L, Tempst P, Villanueva J.  Pathway-based biomarker search by high-throughput proteomics profiling of secretomes. J. Proteome Res. 2009 Mar; 8(3): 1489-503
  • Villanueva J, Nazarian A, Lawlor K, Yi SS, Robbins RJ, Tempst P.  A sequence-specific exopeptidase activity test (SSEAT) for “functional” biomarker discovery. Mol. Cell Proteomics 2008 Mar; 7(3): 509-18
  • Villanueva J, Philip J, DeNoyer L, Tempst P.  Data analysis of assorted serum peptidome profiles. Nat Protoc 2007; 2(3): 588-602
  • Villanueva J, Lawlor K, Toledo-Crow R, Tempst P.  Automated serum peptide profiling. Nat Protoc 2006; 1(2): 880-91
  • 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. Mol. Cell Proteomics 2006 Oct; 5(10): 1840-52
  • Villanueva J, Shaffer DR, Philip J, Chaparro CA, Erdjument-Bromage H, Olshen AB, Fleisher M, Lilja H, Brogi E, Boyd J, Sánchez-Carbayo M, Holland EC, Cordon-Cardo C, Scher HI, Tempst P. Differential exoprotease activities confer tumor-specific serum peptidome patterns. J. Clin. Invest. 2006 Jan; 116(1): 271-84
  • Villanueva J, Philip J, Entenberg D, Chaparro CA, Tanwar MK, Holland EC, Tempst P.  Serum peptide profiling by magnetic particle-assisted, automated sample processing and MALDI-TOF mass spectrometry. Anal. Chem. 2004 Mar; 76(6): 1560-70