I am writing to express my gratitude for being selected as a Grunebaum Research Fellow for a second one-year term. I sincerely appreciate the support and I will do my best to meet the expectations.
Last year, under the support from the Karin Grunebaum Cancer research Foundation, has been a productive one for my laboratory. We have published two research manuscripts in very respected journals like Nature communications and the Journal of Biological Chemistry that advance our knowledge on the molecular mechanism that drive metastasis. Three additional manuscripts have been submitted and we hope that they will get published this coming year. We have also made very significant advance in a drug discovery campaign to identify chemical compounds to inhibit metastasis. The preliminary results from this porject were presented by Dr. DiGiacomo, a postdoctoral fellow in my laboratory, as an oral presentation for Cancer Pharmacology Division in the anual meeting of ASPET (part of the Experimental Biology 2017 meeting in Chicago). He was one of the 3 selected topics for an oral presnetation out of >40 abstracts submitted to this Division. Now we hope to further advance this project to preclinical testing of drugs in animals, for which we are also trying to attract additional funding from Federal agencies. The support from the Karin Grunebaum Cancer Research Foundation will be critical to maintain this project fully active.
In terms of career development activities, during this last year I have been appointed as a member of the Editorial Board of the Journal of Biological Chemistry (5-year term) and also as a member of the MIST Study Section of the NIH (6-year term), which add to my ongoing service as a reviewer in the American Cancer Society.
The insufficient mechanistic information on metastasis has precluded the development of efficient therapeutics for it. The Gα-Interacting, Vesicle-associtated (GIV) protein is emerging as a very promising candidate to become one of the “master regulators” of metastasis and as such, its characterization may open new avenues for therapeutic intervention.
By a combination of biochemical and structural techniques, including nuclear magnetic resonance (NMR) spectroscopy, we have uncovered the molecular mechanism behind GIV binding and activation of a G protein. G proteins are components of the communication system the body uses to sense hormones in the bloodstream and send the corresponding messages to cells.
The results show that the mode of action of GIV differs from the well known G protein coupled receptors (GPCRs) that typically activate G proteins, because it binds to a different region. Molecular modelling and NMR data inform about the protein-protein interface and show that GIV binds to a cavity on the surface of the G protein. These results suggest and allosteric regulation mechanism as conformational changes in one site propagate to another distant site in the molecule. Moreover, this study identifies a novel “druggable” site that could be explited to develop novel tehrapuetic agents against metastasis. This is an ongoing and very active effort of our laboratory.
The work has been the result of a close collaboration between the group of Mikel García-Marcos at Boston University, and the group of Francisco J Blanco at CIC bioGUNE, and has appeared in the journal Nature Communications (https://www.nature.com/articles/ncomms15163). The synergy between the two teams, and the participation or researchers from IRB Barcelona, Cornell University, and University of Glasgow has made it possible to uncover this novel mode of action of a G protein regulator. Multidisciplinary studies of this kind are key to characterize the complex biological processes relevant in biomedical cancer research.
Molecular mechanism of Gαi activation by non-GPCR proteins with a Gα-Binding and Activating motif. A Ibáñez de Opakua, K Parag-Sharma, V DiGiacomo, N Merino, A Leyme, A Marivin, M Villate, LT Nguyen, MA de la Cruz-Morcillo, JB Blanco-Canosa, S Ramachandran, George S Baillie, RA Cerione, FJ Blanco, M Garcia-Marcos (2017) Nature Commun 8, 13935.
We are pleased to announce that our paper entitled “Membrane Recruitment of the Non-receptor Protein GIV/Girdin Is Sufficient for Activating Heterotrimeric G Protein Signaling.” has been published in the Journal of Biological Chemistry. This paper provides novel insights into the molecular mechanisms by which tumor cells sense and respond to their environment to become metastatic. GIV (aka Girdin) is a protein expressed at abnormally high levels in metastatic cancer cells. Although it was known that this protein is important to make tumor cells more invasive and metastatic, the molecular mechanisms underlying this process are still not clear. In our recently published work, we used a combination of chemogenetics, cell biology and real-time signaling biosensors to show that the critical event to activate GIV’s activity in cells is its spatial relocalization. Just by moving from one compartment to another inside the cell, GIV can trigger the signaling pathways that are hyperactive in cancer. These findings further our understanding of the molecular basis of cancer progression and set the basis to identify new vulnerabilities of metastatic cancers. This paper is the result of a joint effort of several people in our lab, but especially of an undergraduate student (Kshitij Sharma) and postdoctoral fellow (Anthony Leyme).
It is a great honor to be the new Karin Grunebaum Fellow! We will keep working hord to meet the expectations!