Joaquín Arribas, PhD
Director, Medical Oncology Research Program
2012-2013 BCRF Project:
Vall d'Hebron University Hospital Research Institute
Senescence, a natural process by which cells "age" and begin to die, can be triggered by an excessive number of cell divisions or a variety of stressors, including oncogenes (also known as cancer-causing genes). While oncogene-induced senescence (OIS) was observed in some studies to impede the expansion of cancer cells, OIS in other studies was reported to actually contribute to tumor progression. The ambiguous role that senescence plays in cancer formation needs further research.
Dr. Arribas, whose lab specializes in research on the HER2 protein, which is over-expressed in 15% to 30% of breast cancers, will undertake a new series of experiments to tackle this question of HER2-induced senescence and its relevance in breast cancer progression. In the group's previous work, an excess of HER2 has shown to be predictive of poor outcome. With funds from BCRF, Dr. Arribas's team identified and validated two novel factors, named HAX-1 and PELO, the levels of which affected cell migration and tumor invasion. These investigators will build on this earlier work to inform their new study of senescence in HER2 breast cancers.
Mid-year Progress: HER2-positive tumors have biological characteristics that allow them to respond to therapeutic options, such as anti-HER2 antibodies and synthetic HER2 inhibitors. A subgroup of HER2-positive tumors express, in addition to the full-length HER2 protein, some HER2 fragments, collectively known as p95HER2, which are particularly active and promote the malignant transformation very efficiently. In fact, p95HER2-positive tumors tend to be particularly aggressive and resistant to the treatment with anti-HER2 antibodies.
During this grant period, Dr. Arribas's team has shown that the expression of p95HER2 in some breast cancer cell lines leads to premature cellular senescence. Senescence is considered a tumor barrier; upon an oncogenic insult, cells react by prematurely aging and, hence, they can no longer proliferate to populate tumors. However, senescent cells induced by p95HER2 remain alive for long periods of time and, paradoxically, they produce a wealth of protumorigenic and prometastatic factors including proteases and growth factors that induce a metastatic behavior in adjacent, non-senescent cells. During the next few months, Dr. Arribas's team will continue characterizing the role of p95HER2-induced senescent cells in the progression of breast cancers and they will compare the senescence induced by p95HER2 with that induced by other oncogenes. These results will allow researchers to understand the role of premature senescence in HER2-positive breast cancers and to design more effective treatments against these tumors.
Joaquin Arribas is the Director of the Medical Oncology Research Program at Vall d'Hebron University Hospital Research Institute, Barcelona, Spain, where he leads a group focused on the study of growth factors, growth factor receptors as well as the proteases involved in remodeling the cell surface. He is a member of the Editorial Board of the Journal of Biological Chemistry, Translational Oncology, and CDB Protein Systems.
Dr. Arribas is member of the Spanish and American Societies of Biochemistry and Molecular Biology and President of the Committee for the Evaluation of research project on Cancer of the "Carlos III" health institute, the major public funding agency in Spain.
Dr. Arribas completed his undergraduate studies in biochemistry at the Autonomous University of Madrid in 1987. At the same university, he subsequently worked on the regulation of the catalytic activities of the proteasome and received a Ph. D. in biology in 1991. Sponsored by a fellowship from the Spanish Ministry of Education and Science, he joined the Memorial Sloan-Kettering Cancer Center (New York, USA) as a postdoctoral fellow to work with Dr. Joan Massague (1992-1996) on the proteolytic processing of transmembrane growth factors. In 1997, he joined the oncology department at Hospital Vall d'Hebron in Barcelona as a staff scientist and was promoted to lead the oncology research department in 2001. His research has been recognized by an EMBO Young Investigator Programme (YIP) award and the Beckman Coulter award to the Best Young Spanish Investigator in Biochemistry and Molecular Biology.