Mentors

Luisa Iruela-Arispe, Ph.D.
Tom Graeber, Ph.D.

Research Interests:

While tumor progression may involve complicated multiple genetic changes, angiogenesis is an essential common mechanism for the development of tumors and the formation of metastasis in solid tumors. Consequently, it has been a target for the treatment of many tumor interventions. I recently found a molecular mechanism that regulates the local level of vascular endothelial growth factor (VEGF), a potent pro-angiogenic growth factor. I showed that in addition to the intracellular pre-mRNA splicing event to generate the soluble versus bound VEGF isoforms, once secreted, ECM-bound VEGF is cleaved intramolecularly by a subset of matrix metalloproteinases (MMPs). MMPs are known to be up-regulated in pathological conditions during tissue repair, inflammation and in cancers. Extracellular cleavage of VEGF results in the release of soluble, receptor-binding domain from the ECM-binding motif that is present in the majority of VEGF-A isoforms. Furthermore, we noted that the state of free versus bound VEGF dictates whether a vascular network undergo dilation/increased vessel size or will initiate active sprouting events, thus promoting two different modes of vascular expansion in tumor models. Therefore, my current research interests are investigating this processing event in real-time by visualizing and quantifying VEGF cleavage, and its relevance to the onset of tumor progression and angiogenesis. I believe that information from these experiments will contribute to further understand the significance of VEGF availability to the onset of tumor progression and will aid in the design of therapeutic strategies to regulate cancer via an anti-angiogenic therapy.

Assistant Professor
Burnham Institute for Medical Research
San Diego, California

Lee SY, Jilani SM, Nikolova GV, Darren Carpizo D, Iruela-Arispe ML. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J. Cell Biol. 2005;169(4):681-691.