Animal Models Laboratory

Juan Angel Recio graduated in biology, specializing in biochemistry, from  the Universidad Complutense de Madrid and holds a master’s degree in Biotechnology. 
In 1997 he moved to Dr. Notarios’s laboratory at the Lombardi Cancer Center, Georgertown University (Washington, DC), where he cloned the human and mouse genes of the proto-cph (pcph) oncogene, elucidated the ectonucleoside triphosphate diphosphohydrolase activity of the protein and its role in carcinogenesis.In 1999 he joined Dr. Merlino’s lab at the National Cancer Institute (NCI, NIH, Bethesda, MD), where he contributed to the discovery of molecular mechanisms underlying signalling of the receptor tyrosine kinase c-MET and how those pathways subverted in malignant melanoma and rabdomyosarcoma.
His achivements in the field of melanoma include the creation of a malignant melanoma mouse model which, is broadly used as a model for UV irradiation within the scientific community. The National Cancer Institute has recognized this line of work with several awards.
He joined to the Medical Oncology Program in December 2004  as Group Leader (Ramon y Cajal Investigator) of the Animal Models and Cancer laboratory. The Group has focused on the discovery of new molecular mechanisms involved in melanoma development and progression and the direct application of this knowledge to developing new therapeutical approaches.

PRINCIPAL INVESTIGATOR

RESEARCH LINES

Novel molecules involved in Melanoma development

Melanoma is the most aggressive type of skin cancer. If metastatic, the median survival is limited to between 6 and 10 months, with no effective treatments available. The genetic, epigenetic and biochemical alterations acquired by melanocytes during tumor development and progression and specifically how they affect treatment response; remain major challenges in skin oncology.

The hepatocyte growth factor (HGF) transgenic malignant melanoma mouse model induced by ultraviolet (UV) radiation represents an interesting opportunity to study this disease. This unique model recapitulates etiologically, chronologically and histopathologically all the stages of the human counterpart including, molecular alterations such as the loss of the p16Ink4a/ARF locus, a relevant genetic mutation associated with human melanoma. The conjunction of these two factors, HGF overexpression and neonatal UV irradiation, were enough to mimic the appropriate context for melanoma development. Following this rationale, the identification of molecules participating in HGF signaling in the UV irradiated melanocytes could provide us with some novel proteins that might be responsible for melanoma development and maintenance. In the past two years we have identified some novel molecules involved in HGF signaling in melanoma neoplastic cell lines obtained from tumors grown in the UV irradiated mouse. Our goal is to focus on proteins that may play a role in human melanoma and whose activation in mice somehow mimics the human condition. We have already focused on two particular proteins that have led to two different subprojects:

Role of LKB1 in melanoma development

Among the molecules identified in the phospho-protein complexes specifically formed in response to HGF was Mo25, a scaffold protein necessary for the activity and correct localization of LKB1 kinase. We further identified LKB1 as a kinase modified in response to HGF and other cancer-related growth factors in a Ras pathway dependent manner. LKB1 is a multitask Serine/Threonine kinase with tumor suppressor activity that participates in a variety of biological processes involved in malignant transformation such as cell cycle control, energy metabolism sensor, gene regulation, apoptosis and cell polarity. However the biological role of LKB1 in response to growth factors is unknown. We recently discovered that oncogenic BRAF and Ras pathway activation by growth factors promotes the uncoupling of LKB1-AMPK complexes, conferring resistance to energy stress, and provides a mechanism to prevent inhibition of protein synthesis and cell growth in response to mitogenic stimulus.

Role of LKB1 in UV-induced skin tumorigenesis

Sporadic mutations in the lkb1 gene have been documented in cancers of the breast, pancreas, lung, prostate, cervix and ovary as well as in Peutz-Jeghers syndrome, a rare disorder characterized by the appearance of intestinal polyps and mucocutaneous melanocytic macules. More importantly, lkb1 mutations have been described in melanoma, and based on this information, we determined whether LKB1 could function as a potential link between an activated RAS pathway and dysfunctional c-Met signaling, and play a role in melanoma development and progression. According to this rationale we have generated several animal models to study the role of LKB1 in UV induced melanoma development and progression.

Arginine Methylation: a post-translational modification modulating signal transduction

We identified arginine methylation as a post-translational modification responsible for the modulation of signal transduction. It is known that several growth factors activate the same signaling pathway. However the biological responses to theses ligands are quite different. Arginine methylation seems to modulate the signal amplitude in order to achieve the appropriate biological response elicited by a particular growth factor. We investigated the fine mechanism involved in this process, identifying the methylase involved in the process. This discovery adds a new level of signal transduction regulation and new candidates for therapeutic intervention.

Preclinical study using PI3K and BRAF spcecific inhibitors

Recent results indicate the PI3K and Ras pathways are particularly relevant in human melanoma development and progression. The use of BRAF specific inhibitors (Sorafenib) as a monotherapy agent has been shown to be ineffective for melanoma treatment. We are combining different inhibitors targeting important pathways in melanoma development and progression to test their efficacy as combined agents in melanoma treatment, in an immunocompetent model. Importantly, this immunocompetent animal model revealed unexpected systemic effects that ultimately modify tumor behavior.

PUBLICATIONS

Callejas-Valera JL, Guinea-Viniegra J, Ramírez-Castillejo C, Recio JA, Galan-Moya E, Martínez N, Rojas JM, Ramón y Cajal S, Sánchez-Prieto R. E1a gene expression blocks the ERK1/2 signaling pathway by promoting nuclear localization and MKP up-regulation: implication in v-H-Ras-induced senescence. J Biol Chem. 83(19):13450-8. Epub 2008 Mar 3.
(IF: 5.581, 1 cuartil, biochemistry & molecular biology)

Esteve-Puig R, Canals F, Colomé N, Merlino G, Recio JA. Uncoupling of the LKB1-AMPK_ energy sensor pathway by growth factors and oncogenic. BRAFV600E. PLoS ONE. In press.

RESEARCH PROJECTS

Funding Agency: European Community (Marie Curie Reintegration Grant)
“Caracterization of novel mechanisms of HGF signaling in melanoma”
P.I: Juan A. Recio
Duration: 2006/Jul 2008

Funding Agency: ISCIII (FIS)
“Mecanismos de actuación del Factor de Crecimiento Hepático (HGF) en la adquisición y progresión del melanoma cutáneo: aplicación del modelo animal de melanoma maligno basado en ratones transgénicos del HGF”
P.I: Juan A. Recio
Duration: 2006/Feb-09

Funding Agency: FMMA
“Papel de LKB1 en melanoma maligno”
P.I: Juan A. Recio
Duration: 2007/Jul-10

Funding Agency: ISCIII (FIS)
Papel de LKB1 en respuesta a factores de crecimiento y en el desarrollo y progresión del melanoma”
P.I: Juan A. Recio
Duration: 2009-2011

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