Growth Factors Laboratory

Joaquín Arribas graduated in biochemistry from the Autonomous University of Madrid in 1987. He received a Ph. D. in biology in 1991.
He joined the Memorial Sloan-Kettering Cancer Center (New York, USA) as a postdoctoral fellow to work with Joan Massagué on the proteolytic processing of transmembrane growth factors. He joined the oncology department at Vall d'Hebron University Hospital in Barcelona as a group leader in 1997, to investigate the role of certain growth factors and their receptors in breast cancer progression and treatment, and was promoted to lead the oncology research department in 2001. He was appointed Research Professor by ICREA (Institució Catalana de Recerca i Estudis Avançats) in 2007.
His research has been recognized by an EMBO Young Investigator Programme (YIP) award and the Beckman Coulter award for the Best Young Spanish Investigator in Biochemistry and Molecular Biology. He is a member of the Editorial Board of the Journal of Biological Chemistry. Translational Oncology and CDB Protein Systems.
He is also member of the Spanish and American Societies of Biochemistry and Molecular Biology and President of the Committee for the Evaluation of Cancer Research Projects of the Carlos III Health Institute.

PRINCIPAL INVESTIGATOR

RESEARCH LINES

Breast cancer is the most common cancer among women, According to the World Health Organization, more than 1.2 million women will be diagnosed with breast cancer each year worldwide and over 500,000 will die from the disease.

Approximately 30% of patients with breast cancer express excessive levels of the tyrosine kinase receptor HER2. The prognosis of these patients is clearly worse than that of patients with normal levels of the receptor. HER2 (ErbB2) belongs to the family of the epidermal growth factor receptor (EGFR), which also includes HER3 (ErbB3) and HER4 (ErbB4). We are currently investigating the relevance of novel isoforms of HER2 in tumor progression and treatment.

The HER signaling pathway

Dimerization of the extracellular domains leads to interaction between the intracellular kinases of the HER receptors and subsequent transphosphorylation of certain tyrosine residues in the C-terminal tail. These phosphotyrosines act as docking sites for a group of intracellular phosphotyrosine-binding proteins that transduce signals from the plasma membrane to the nucleus via different signaling pathways, including the mitogen activated protein kinases (MAPKs), PI(3)K-activated Akt, Src and phospholipase C gamma (PLCgamma) pathways. These signaling circuits control the expression of target genes that act in coordination to modify key aspects of cellular biology, including proliferation, migration, survival and differentiation.

Novel signaling abilities of HER receptors and fragments of them

In addition to the canonical mode, HER receptors or fragments of them seem to be endowed with direct signaling abilities. HER2 is a substrate of metalloproteases collectively known as alpha-secretases, which release the extracellular domain, leaving behind the transmembrane-cytoplasmic fragment, known as P95. By analogy with other transmembrane proteins also cleaved by alpha-secretases, it has been suggested that the cleavage of P95 can also be achieved by gamma-secretases, which release the intracellular domain in a process known as RIP (regulated intramembrane proteolysis). Although P95 has been poorly characterized, partly because it is produced at very low levels in cultured cell lines, it has been suggested that it is active. However, since P95 lacks the extracellular domain, it is not predicted to form hetero- or homodimers. Thus, the mechanism of activation of P95 remains unexplained.

We have recently identified alternative initiation of translation as an additional mechanism that generates CTFs of HER2 similar, but not identical, to P95. Initiation of translation from methionine codons, located upstream or downstream of the transmembrane domain, leads to the generation of two different CTFs (Fig. 1). Although preliminary evidence suggests that CTFs generated by translation are active, as in the case of P95, the mechanism of activation is unknown.

In summary, at least four different HER2 CTFs are generated by two independent mechanisms: proteolytic processing and alternative initiation of translation (Fig. 1). Two HER2 CTFs contain the transmembrane and cytoplasmic domains while two are predicted to be soluble intracellular proteins encompassing most of the cytoplasmic domain (Fig 1).

HER2 fragments and breast cancer progression and treatment

Breast cancer patients expressing CTFs of HER2 are more likely to develop nodal metastasis and have worse prognosis than those expressing predominantly the full-length receptor. Furthermore, the presence of CTFs seems to be relevant for tumor treatment. Currently, two types of drugs targeting HER2 are used in clinical practice: monoclonal antibodies against the extracellular domain and small-molecule inhibitors that block the kinase activity of the receptor. We have recently shown that approximately 90% of breast cancer patients expressing CTFs are resistant to treatment with the anti-HER2 antibody Herceptin (trastuzumab). However, the CTFs expressed in tumors have not been characterized in detail and it is not known if these fragments arise in tumors by proteolysis and/or alternative initiation of translation. Furthermore, since the activity of the different CTFs has not been analyzed individually, their relative contribution to the malignant phenotype has not been determined.

Characterization of HER2 fragments>

In 2008 we finished a comprehensive analysis of the different CTFs of HER2 expressed in breast cancers. The characterization of cells lines individually expressing different CTFs showed that the activity of P95 is comparable to that of full-length HER2. In contrast, the product of alternative initiation of translation from methionine 611 is hyperactive and specifically controls the expression of genes involved in malignant transformation and metastasis. In contrast, CTFs devoid of a transmembrane domain appear to be inactive. Finally, we have established transgenic mouse models to show that expression of 611-CTF leads to the generation of tumors far more aggressive than those generated by full-length HER2.

PUBLICATIONS

Esselens C, Malapeira J, Canals F, Moss M and Arribas J. Metastasis-associated C4.4A, a GPI-anchored proteína cleaved by ADAM10 and ADAM17. Biol Chem. 2008 Aug;389(8):1075-84.
(IF: 2.840, 2 cuartil, biochemistry molecular biology)

Scaltriti M, Verma C, Guzman M, Jiménez J, Parra JL, Pedersen K, Smith DJ, Landolfi S, Ramón y Cajal S, Arribas J, Baselga J. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. In press.
(IF: 6.440, 1 cuartil, oncology)

Vilar E, Scaltriti M, Balmaña J, Saura C, Guzman M, Arribas J, Baselga J, Tabernero J. Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines. Br J Cancer. 2008 Nov 18;99(10):1607-12. Epub 2008 Oct 21.
(IF: 4.635, 1 cuartil, oncology)

Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008 Oct 1;68(19):8022-30.
(IF: 7.672, 1 cuartil, oncology)

RESEARCH PROJECTS

Funding Agency: Asociación Española Contra el Cáncer
Title: "Caracterización funcional y estructural contra el cáncer de un nuevo producto del proto-oncogén HER2.Implicaciones terapéuticas en cáncer de mama".
PI: Joaquín Arribas
Duration: April 2005 - April 2008

Funding Agency: Fundación la Caixa
Title: "Identificación del degradoma de la metaloproteasa desintegrina TACE: relevancia en el desarrollo de tumores de mama"
PI: Joaquín Arribas
Duration: 2005 - August 2008

Funding Agency: Ministerio de Educación y Ciencia
Title "Generación y caracterización de ratones transgénicos expresando Fragmentos C-Terminales del oncogén HER2 en glándulas mamarias".
PI: Joaquín Arribas
Duration: 2005 - October 2008

Funding Agency: Fundació La Marató de TV3
Title: "Identificació i caracterització dels mecanismes de tumorogenesis mediats pels fragments carboxiterminals de HER2".
PI: Joaquín Arribas
Duration: 2006 - December 2008

Funding Agency: Fundacion MUTUA MADRILEÑA(FMM)
Title: "Identificación de mecanismos y factores involucrados en la sobreexpresión y tráfico intracelular de ADAM17(TACE).Relevancia para el desarrollo de tumores de mama".
PI: Joaquín Arribas
Duration: 2007 - July 2010

Funding Agency: Instituto Carlos III (Subdirección General de Redes y Centros
de Investigación Cooperativa)
Title: "Red Temática de Investigación Cooperativa del Cáncer".
PI: Joaquín Arribas
Duration: 2007 - 2010

Funding Agency: Generalitat de Catalunya (AGAUR)
Title: "SGR Suport a Grups de Recerca de Qualitat".
PI: Joaquín Arribas
Duration: 2006 - December 2008

Funding Agency: Genoma España
Title: "Proteored"
PI: Joaquín Arribas
Duration: 2005 - 2010

Funding Agency: The Breast Cancer Research Foundation
Title: "Identification of factors and mechanisms leading to metastasis in breast tumors expressing HER2 Carboxy Terminal Fragments."
PI: Joaquín Arribas
Duration: 2007 - 2008

Funding Agency:The Breast Cancer Research Foundation
Title: "Metastasis in tumors expressing 611-CTF of HER2: mechanisms an d therapeutics strategies."
PI: Joaquín Arribas
Duration: 2008 - 2009

Funding Agency: Instituto Carlos III
Title: "Fragmentos Carboxilo Terminales (CTFS) en la progresión y tratamiento del cáncer de mama"
PI: Joaquín Arribas
Duration: 2009 - 2012

Funding Agency: Compugen
Title: "Service Agreement"
PI: Joaquín Arribas
Duration: 2009 - 2011

Back to list