Research lines:
1. Autophagy in the Vascular Peritumoral Niche during Glioblastoma progression:
Glioblastoma multiforme (GB), is the most aggressive brain tumor, with no cure actually. Our preliminary results determine that we can find an effective cure to eliminate the GB tumor growth through modulation of a molecular mechanism known as chaperone-mediated autophagy (CMA) in brain defense-perivascular cells called pericytes (PC). As CMA is universal in all types of cells, including tumor cells, is required the better understanding of the biology of the niche that surrounds the tumor to find target specific markers and stablish an effective selective therapy.
We study the role of autophagy in the immune function of perivascular cell populations in brain that present stem cell properties and inflammatory function that might be modulated for cell therapy in pathologies assocciated to neurodegeneration and in Glioblastoma Multiforme progression. Our first goal is understand the molecular mechanisms implicated in the evasion of the perivascular immune response during interaction and perivascular infiltration of the tumor cells in the GB, and therefore, to determine what types of autophagy and their functions might be implicated.
Autophagy is known for its various regulatory roles in immune cells. The ability of autophagy to degrade regulation intermediaries in immune cells and the increasingly frequent use of autophagy inhibitors in clinical trials makes it a possible candidate to modulate the immune response of perivascular stem cells of brain that are implicated in several neurodegeneration pathologies and assist the GB.
Our group is mainly studying how autophagy is regullated and affects other functions of brain perivascular cells and its implication in the vascular changes and perivascular infiltration of tumor cells during GB. Our objectives are based on our previous results, Macroautophagy (MA), as a bulk degradation process in perivascular immune cells, might be implicated in the energetic metabolism and remodelling required for the interaction with the tumor cells, whereas Chaperone Mediated Autophagy (CMA), as a high selective process in its degradation of proteins, consequently could be important in the reprogramming of immune phenotype (through proteome changes) induced upon interaction with GB cells. We are testing different drus to try to modulate CMA. Furthermore, we have identified several markers in our glioblastoma murine model that are starting to be validated in human-derived biopsies of GB patients, which are selected and previously studied by MNR. We believe that finding better ways of early diagnosis and prognosis and an effective therapy would increase the life expectancy of patients and reduce the cost of treatments.
2. Autophagy in Stem Cells and Pericytes, Cell Therapy: We are developing experimental models to demonstrate the neurotropic and immuno-regulator potential of bone marrow stromal cells and pericytes. We work in animal models of demyelinating diseases (multiple sclerosis) and neurodegenerative (cerebellar ataxia cord and amyotrophic lateral sclerosis) where we are seeing that hematopoietic and stromal stem cells have a trophic and partially regenerative effect. Our studies are the basis to to get efficient therapies and demonstrate that we can modulate the mesenchymal properties of pericytes and stem cells through modulation of autophagy, mainly chaperone-mediated autophagy. We are involved in cell therapy clinical trials to promote symptom attenuation in neurodegenerative diseases using cells as neurotrophic factor factories and immunoregulatory properties.
Collaborations with IMIB groups:
Our studies are also in collaboration with other groups of IMIB-Arrixaca, such as the Cell therapy group in which Dr. J.M. Moraleda is the principal investigator. Dr. D.Garcia Bernal is also and important collaborator of this group in our studies on the stem cells biology. They are collaborating in all current research lines of the group.
We also collaborate with the ¨brain regionalization and gene development¨group of IMIB-Arrixaca, studying the biology and cell interactions of the brain tumor.
Dr. Pablo Pelegrin´s group, ¨molecular inflammation¨ group is also a strong collaborator and scientific advisor in our current research lines and on that related to the inflammatory response.
In addition, we have important collaboration with the group of Professor Pedro Aparicio and Dr. Gonzalo Rubio titled as ¨signals transmission in the the immune system¨ in the Biochemistry, Molecular biology B and Immunology department, in University of Murcia. They collaborate tighly in a current research project on the glioblastoma research line.
National and international collaborations:
For our studies on autophagy, our recent formed group caters with the international collaboration of labs of expertise in ´´Autophagy in the tumor biology and immune system´´, such as Dr. A.M. Cuervo and F. Macian labs in Albert Einstein College of Medicine, New York, and with the essential tools (autophagy reporters, lentiviral vectors expressing shRNAs for different autophagy proteins, LAMP-2A deficient mice…) to characterize those processes that will be available to us to further achieve the goals of our studies. They are our scientific advisors in the cell proteostasis mechanisms and in the immunosuppressive and tolerant immune response.
We also have the expert advice of molecular biology, and gene analysis and edition of our national collaborators, Dr. J. Lopez-Atalaya (Instituto de Neurociencias, Alicante), Dr. Felipe Prosper and Dr. J. Rodriguez-Madoz (Centro de investigación medica aplicada de Pamplona, FIMA). We also have the support of Prof. S. Muller (University of Strasbourg; expert in pharmacological therapies in other disease models with their own CMA inhibitors).
Future goals:
Glioblastoma multiforme (GB), is the most aggressive brain tumor, with no cure actually that produces high mortality, without effective current treatment and an average survival of less than one year. To this contributes the ignorance of its pathogenesis and the mechanisms of disease progression. Our previous results determine that we can find an effective cure to eliminate the GB tumor growth through modulation of chaperone-mediated autophagy (CMA) in brain defense-perivascular cells, PC.
As CMA is universal in all types of cells, including tumor cells, is required the better understanding of the biology of the niche that surrounds the tumor to find target specific markers and stablish an effective selective therapy to treat this aggressive cancer.
With the help of our international collaborators, we have been able to evidence the ability of GB-induced CMA in PC to selectively degrade specific proteins, and therefore, to ablate PC immune function. Therefore, this mechanism becomes into an attractive candidate to target, knowing its regulation and the different signaling intermediates substrates to modulate the immune response in the perivascular niche in PC, in response to GB interaction under several stressors. Furthermore, identification of degraded specific proteins and other important functions of PC that modulate tumor progression, may constitute promising new target mechanisms to treat this aggressive cancer. Gene therapy directed to CMA only by blocking LAMP2A expression or functionality could provide a much greater specificity to the anti-cancer strategies. In addition, once specific markers of GB-conditioned PC are identified, we can initiate a protocol to develop selective immunotherapy against tumor PC (future project). Then, preclinical studies of combined immunotherapies able to cross blood-brain barrier or by intrathecal therapy, could prevent side effects from other immune cells different to PC.
Furthermore, understand cancer-PC interaction seems relevant to know cellular mechanisms underlaying tumor growth and metastatic niche generation. Thus, the identification of several markers will further facilitate a better diagnosis and successful prognosis of this aggressive cancer.
The achievement of our objectives can have a huge scientific and international impact, since for the first time the natural history of glioblastoma disease could be positively altered. This would result in the obtaining of patents and possibly new products for therapy in other diseases associated with autoimmunity and rejection in transplantation, since the pericyte could be used as a cell immunomodulated by CMA. It is important to highlight that in the coordination and evaluation of our group, the work will be carried out in a hospital setting and biomedical research institution, in the context of a multidisciplinary group of basic and clinic researchers and with the help of international recognized basic science groups in CMA, immunological tolerance, neuroscience and therapy. And therefore, the future goal is to improve the diagnosis, prognosis and stablish the basis for the realization of a clinical therapy study to finally increase the survival of GB `patients.
