O receptor Ror1 e seu papel em câncer

Las proteínas Wnt son ligandos que activan señales involucradas en proliferación, sobrevida, adhesión, migración, diferenciación y polaridad celular y como tal están involucradas en una amplia variedad de patologías. A diferencia de la vía Wnt canónica (o dependiente de beta-catenina) la vía no canónica posee numerosas ramificaciones y ha sido muy poco estudiada. Evidencias obtenidas en los últimos años sugieren que la vía Wnt no canónica (a través de Wnt5a) jugaría un importante rol en la progresión de numerosos tipos de tumores, incluyendo melanoma. Tradicionalmente, la mayor parte de la señalización por Wnt ha sido atribuida a la activación de Fzd y LRP. Sin embargo, evidencias mas recientes indican que Wnt puede ejercer sus efectos a través de receptores alternativos Ror1 y 2 (receptor huérfano 1 y 2 similar a tirosina quinasa). Estas proteínas son receptores de Tirosina Quinasa con una arquitectura funcional excepcional dentro de su familia ya que son los únicos en poseer dominios Kringle y dominios ricos en serina y treonina en el extremo C-terminal. Originalmente clonados como receptores huérfanos, su caracterización como receptores Wnt es relativamente reciente por lo cual su rol está en proceso de ser dilucidado.Wnts are ligands that stimulate several signal transduction pathways involved in cell proliferation, survival, migration, and differentiation. Wnt pathway malfunction has been implied in various forms of disease. The most extensively studied Wnt pathway, termed canonical, results in stabilization of β-catenin and activation of gene expression by TCF and LEF transcription factors. However, Wnts can also activate numerous non-canonical pathways which are independent of β-catenin. These non-canonical pathways have been much less studied. Recent evidences suggest that the Wnt non-canonical pathway (via Wnt5a) would play an important role in several types of cancer, including melanoma. The Wnt signaling has usually been related to activation of Fzd and LRP receptors. However, more recent data indicate that Wnt can activate the alternative receptors Ror1 and 2 (receptor tyrosine kinase-like orphan receptor 1 and 2). These proteins belong to the Tyrosine kinase family and have particular functional domain such as the Kringle domains and Serine/Threonine domains at the C-terminal. Originally cloned as orphan receptors, they were more recently characterized as Wnt receptors and their cellular role is being elucidated.As proteínas Wnt são ligandos que ativam sinais envolvidos em proliferação, sobrevida, adesão, migração, diferenciação e polaridade celular e como tal estão envolvidas numa ampla variedade de patologias. À diferença da via Wnt canônica (ou dependente de beta-catenina) a via não canônica possui numerosas ramificações e tem sido muito pouco estudada. Evidências obtidas nos últimos anos sugerem que a via Wnt não canônica (através de Wnt5a) teria um importante papel na progressão de numerosos tipos de tumores, incluindo melanoma. Tradicionalmente, a maior parte da sinalização por Wnt tem sido atribuída à ativação de Fzd e LRP. Entretanto, evidências mais recentes indicam que Wnt pode exercer seus efeitos através de receptores alternativos Ror1 e 2 (Receptor tyrosine kinase-like orphan receptor 1 and 2). Estas proteínas são receptores de Tirosina Quinase com uma arquitetura funcional excepcional dentro de sua família já que são os únicos em possuir domínios Kringle e domínios ricos em serina e treonina no extremo C-terminal. Originalmente clonados como receptores órfãos, sua caracterização como receptores Wnt é relativamente recente pelo qual seu papel está em processo de ser elucidado.Fil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin

ROR2, a driver of “phenotype switching” in melanoma?

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a receptor for the Wnt5a ligand that was shown to play a dual role in cancer. ROR2 was shown to either suppress or promote tumor progression in different tumor types by regulating the same biological processes (i.e. proliferation, invasion) in opposite ways. We have recently observed that ROR2 plays multiple and somewhat contradictory roles in melanoma where it impairs cell proliferation but promotes migration, EMT and chemoresistance. In the present article, ROR2 is proposed to be a major driver of “phenotype switching” in melanoma that can tilt the cellular behavior toward proliferative or invasive phenotypes. This function of ROR2 has therapeutic implications since it would provide an opportunity for targeting specific phenotypes such as invasive and drug-resistant ones by inhibiting ROR2.Fil: Lopez Bergami, Pablo Roberto. Universidad Maimónides; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Melanoma: Diagnóstico, evolución y tratamiento bajo una perspectiva molecular

La incidencia de cáncer de piel y particularmente de melanoma se encuentra en franco ascenso debido a la combinación de factores ambientales y socio-culturales. A diferencia de otros tipos de tumores malignos, en la mayoría de los casos la aparición de esta enfermedad y/o sus consecuencias más graves pueden preverse simplemente a través de cambios en nuestras conductas. Fundamentalmente, se recomienda tomar mayores recaudos al exponernos a la radiación ultravioleta y seguir los consejos médicos para la detección precoz de lesiones cutáneas potencialmente peligrosas. El objetivo del presente artículo es proporcionar a los lectores un mayor conocimiento acerca de los distintos aspectos de esta enfermedad, tales como los factores de riesgo, su diagnóstico y pronóstico. También se intenta informar sobre los avances más recientes en el campo de la investigación y como estos descubrimientos están siendo aplicados para mejorar el tratamiento de los pacientes que sufren esta enfermedad.Fil: Picco, María Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Fernández, Natalia Brenda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentin

The EphB4 receptor promotes the growth of melanoma cells expressing the ephrin-B2 ligand

Cutaneous melanoma is the most aggressive form of skin cancer and several families of receptor tyrosine kinases have been implicated in its development and progression, including the Eph receptor family (Hess et al., 2007; Smalley et al., 2009). Among Eph receptors, EphA2 has been most extensively studied in melanoma and linked to increased malignancy (Hess et al., 2007; Margaryan et al., 2009).Fil: Yang, Nai Ying . University of California; Estados UnidosFil: Lopez Bergami, Pablo Roberto. Sanford-burnham Medical Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Goydos, James S.. Robert Wood Johnson Medical School; Estados UnidosFil: Yip, Dana . Robert Wood Johnson Medical School; Estados UnidosFil: Walker, Ameae . University of California; Estados UnidosFil: Pasquale, Elena B.. Sanford-burnham Medical Research Institute; Estados UnidosFil: Ethell, Iryna. University of California; Estados Unido

BCL2l10 is overexpressed in melanoma downstream of STAT3 and promotes cisplatin and ABT-737 resistance

The anti-apoptotic proteins from the Bcl-2 family are important therapeutic targets since they convey resistance to anticancer regimens. Despite the suspected functional redundancy among the six proteins of this subfamily, both basic studies and therapeutic approaches have focused mainly on BCL2, Bcl-xL, and MCL1. The role of BCL2L10, another member of this group, has been poorly studied in cancer and never has been in melanoma. We describe here that BCL2L10 is abundantly and frequently expressed both in melanoma cell lines and tumor samples. We established that BCL2L10 expression is driven by STAT3-mediated transcription, and by using reporter assays, site-directed mutagenesis, and ChIP analysis, we identified the functional STAT3 responsive elements in the BCL2L10 promoter. BCL2L10 is a pro-survival factor in melanoma since its expression reduced the cytotoxic effects of cisplatin, dacarbazine, and ABT-737 (a BCL2, Bcl-xL, and Bcl-w inhibitor). Meanwhile, both genetic and pharmacological inhibition of BCL2L10 sensitized melanoma cells to cisplatin and ABT-737. Finally, BCL2L10 inhibited the cell death upon combination treatments of PLX-4032, a BRAF inhibitor, with ABT-737 or cisplatin. In summary, we determined that BCL2L10 is expressed in melanoma and contributes to cell survival. Hence, targeting BCL2L10 may enhance the clinical efficacy of other therapies for malignant melanoma.Fil: Quezada, Maria Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Picco, María Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Villanueva, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Castro, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Barbero, Gastón Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Fernández, Natalia Brenda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Illescas, Edith. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentin

Filamin a expression negatively regulates Sphingosine-1-phosphate-induced NF-κB activation in melanoma cells by inhibition o Akt signaling

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that regulates many processes in inflammation and cancer. S1P is a ligand for five G-protein-coupled receptors, S1PR1 to -5, and also has important intracellular actions. Previously, we showed that intracellular S1P is involved in tumor necrosis factor alpha (TNF)-induced NF-κB activation in melanoma cell lines that express filamin A (FLNA). Here, we show that extracellular S1P activates NF-κB only in melanoma cells that lack FLNA. In these cells, S1P, but not TNF, promotes IκB kinase (IKK) and p65 phosphorylation, IκBα degradation, p65 nuclear translocation, and NF-κB reporter activity. NF-κB activation induced by S1P was mediated via S1PR1 and S1PR2. Exogenous S1P enhanced the phosphorylation of protein kinase Cδ (PKCδ), and its downregulation reduced S1P-induced the phosphorylation of IKK and p65. In addition, silencing of Bcl10 also inhibited S1P-induced IKK phosphorylation. Surprisingly, S1P reduced Akt activation in melanoma cells that express FLNA, whereas in the absence of FLNA, high phosphorylation levels of Akt were maintained, enabling S1P-mediated NF-κB signaling. In accord, inhibition of Akt suppressed S1P-mediated IKK and p65 phosphorylation and degradation of IκBα. Hence, these results support a negative role of FLNA in S1P-mediated NF-κB activation in melanoma cells through modulation of Akt.Fil: Campos, Ludmila Estefanía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Rodriguez, Yamila Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Machado Leopoldino, Andreia. Virginia Commonwealth University. School of Medicine; Estados Unidos. Universidade de Sao Paulo; BrasilFil: Hait, Nitai C.. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Lopez Bergami, Pablo Roberto. Universidad Maimonides; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Castro, Melina Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Sanchez, Emilse Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Maceyka, Michael. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Spiegel, Sarah. Virginia Commonwealth University School Of Medicine;Fil: Alvarez, Sergio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentin

The long arm of BRAF V600E gets to mTORC1

Despite the disappointing results of early clinical studies, targeting the BRAF ⁄ MEK⁄ extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK) pathway is still a subject of investigation due to its biological relevance to melanoma. It is now evident that to antagonize redundant protein functions and compensatory signaling pathways BRAF inhibitors must be combined with inhibitors of other relevant pathways based on a strong rational basis. Thus, we must expand our understanding of MAPK effectors and how MAPK interacts with those other pathways.Fil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Cell death in response to genotoxic stress and DNA damage:

Cells are subjected to multiple types of stress throughout their life cycle, including starvation, infection, and physical and chemical agents. Stressors cause transient and permanent damage. Transient damage is reflected at the level of the protein or RNA and is largely associated with the generation of reactive oxygen radicals, which directly or indirectly impact translation, folding, or conformation of proteins. In contrast to transient damage, which is expected to be cleared by existing cellular machinery that allows recognition and removal of damaged proteins, permanent damage is primarily reflected at the level of the DNA, although it could also result from damaged proteins that fail to support proper repair or cell duplication. DNA-damaging agents induce a variety of modifications that may result in improper chromosomal duplication, recombination between chromosomes, gene mutations, or gene amplification, which may result in malignant transformations if not properly repaired. Damage is generated by both endogenous and exogenous sources: endogenous (spontaneous) damage is caused by agents within the cell itself (i.e., the products of normal cellular metabolism, replication, mitosis), whereas exogenous sources include ultraviolet (UV) light, ionizing radiation (IR), and environmental genotoxins (e.g., alkylating compounds, polycyclic aromatic hydrocarbons, biphenyls, and heterocyclic amines). Most cytotoxic anticancer drugs react either directly or indirectly (through reactive metabolites) with DNA or by blocking DNA-metabolizing functions, such as DNA polymerases or topoisomerases.Fil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Zeev, Ronai. Sanford-burnham Medical Research Institute; Estados Unido

The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment

Wnt5a is the prototypical activator of the non-canonical Wnt pathways, and its overexpression has been implicated in the progression of several tumor types by promoting cell motility, invasion, EMT, and metastasis. Recent evidences have revealed a novel role of Wnt5a in the phosphorylation of the NF-κB subunit p65 and the activation of the NF-κB pathway in cancer cells. In this article, we review the molecular mechanisms and mediators defining a Wnt5a/NF-κB signaling pathway and propose that the aberrant expression of Wnt5a in some tumors drives a Wnt5a/NF-κB/IL-6/STAT3 positive feedback loop that amplifies the effects of Wnt5a. The evidences discussed here suggest that Wnt5a has a double effect on the tumor microenvironment. First, it activates an autocrine ROR1/Akt/p65 pathway that promotes inflammation and chemotaxis of immune cells. Then, Wnt5a activates a TLR/MyD88/p50 pathway exclusively in myelomonocytic cells promoting the synthesis of the anti-inflammatory cytokine IL-10 and a tolerogenic phenotype. As a result of these mechanisms, Wnt5a plays a negative role on immune cell function that contributes to an immunosuppressive tumor microenvironment and would contribute to resistance to immunotherapy. Finally, we summarized the development of different strategies targeting either Wnt5a or the Wnt5a receptor ROR1 that can be helpful for cancer therapy by contributing to generate a more immunostimulatory tumor microenvironment.Fil: Lopez Bergami, Pablo Roberto. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico. Departamento de Estudios Biomédicos y Biotecnológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barbero, Gastón Alexis. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico. Departamento de Estudios Biomédicos y Biotecnológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin