Science

Since my early teens I wanted to become a scientist.

Luckily for me, the circumstances allow me to graduate as a Biologist and Biochemist at my city, Pamplona. Soon after finishing my bachelor studies I commenced my Ph.D. studies.

During my training I had the fortune to work in numerous countries, with hundreds of scientists and medical doctors. I could learn techniques and background in different disciplines, ranging from Molecular Biology, Cellular Biology, Microscopy, Histology, Cancer Research, Biochemistry, Biotechnology, Immunology, and Physiology.

I was always fascinated by the tumor vasculature (see picture attached). In my years of Ph.D. Angiogenesis (the process by which tumors generate new vessels from preexisting ones) was a major focus in cancer biology studies. Chief therapy design efforts were on the direction of blocking this tumor-inherent process. My main topic during the Ph.D. studies was the study of different isoforms of VEGF, a chief angigogenesis-promoting molecule.

My principal contributions to cancer research in my Ph.D. are.

1. Discovery that diffusible (short) VEGF isoforms as potently active in vivo (as opposed to the notion of longer isoforms to be stronger activating the VEGF receptors in the target cells) in prostate cancer models. This observation was shown to be of clinical relevance as patients with prostate cancer display a shift towards the expression of these short, more biologically active isoforms. This likely occurs due the deregulation of an important molecular process name mRNA-Splicing.

In this study I came up with an elegant molecular trick to shift mRNA isoforms of VEGF without excessive over expression or repression of single isoforms; the use of Morpholino artificial oligonucleotides, which shifts the proportions of isoforms exactly as observed in human patients.

2. Refuting the notion that the so-called VEGFxxxb isoforms are antiangiogenic. After years of following a lead by other research group, I finally concluded that such isoforms (which I generated artificially in the laboratory by means of genetic engineering, and biochemical methods of protein purification based on affinity chromatography since we could not actually detect them in any living system) are not antiangiogenic, but weakly angiogenic. This observation is corroborated by other studies. This study is an example of the importance negative results have for science, and the necessity of multiple laboratories to cross-compare results.

3. Discovery of VEGF as a metastasis enhancing factor through the up regulation of Tenascin-C. I was the first one to demonstrate that Tenascin-C (an extracellular matrix protein) is able to boost metastasis of mammary tumors to the lung. By molecular ablation of this protein using iRNA, we could show a decrease in the metastasis affection in mouse experimental models. These results were nicely replicated some years later by the reputed metastasis scientist Dr. Massagué.

4. Elucidation of tumor stromal pathways that block bone-metastasis. This is my favorite work during the Ph.D. program. A drug called sunitinib did not have absolutely any effect on the growth of an aggressive lung cancer tumor cell line in a petri dish, even at very high concentrations. However, when administered to mice engineered to develop bone metastasis with the same cells, this compound dramatically stopped metastasis, and double the survival time of these mice, compared to untreated mice. We found the cellular and molecular target for this drug in the microenvironment (The PDGFRbeta receptor on bone-marrow reticular cells). This study underlines the importance of the tumor microenvironment, and how tumors can be efficiently blocked by targeting other types of cells.