Person:
Segura-Collar, Berta

First Name

Berta

Last Name

Segura-Collar

Institution

ISCIII

Centrre

ISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)

Identifiers

Full item page

Search Results

Now showing 1 - 10 of 11

Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype.
(Multidisciplinary Digital Publishing Institute (MDPI), 2020-11-02) Cejalvo, Teresa; Gargini, Ricardo; Segura-Collar, Berta; Mata-Martínez, Pablo; Herranz, Beatriz; Cantero, Diana; Ruano, Yolanda; García-Pérez, Daniel; Pérez-Núñez, Ángel; Ramos, Ana; Hernández-Laín, Aurelio; Martín-Soberón, María Cruz; Sánchez-Gómez, Pilar; Sepúlveda-Sánchez, Juan Manuel; Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española Contra el Cáncer; Ministerio de Ciencia, Innovación y Universidades (España); Fundación Sociedad Española de Oncología Médica
Gliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to explain this lack of response and to improve the therapy of glial tumors. We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocitrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in syngeneic mouse models. We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous. Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the percentage of leukocytes and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic allografts of GL261 cells, delaying tumor growth. We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. By contrast, in IDH1/2 wild-type gliomas, we have found a direct correlation between the presence of vascular alterations and the entrance of leukocytes into the tumors. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules.
The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas
(Multidisciplinary Digital Publishing Institute (MDPI), 2020-01-14) Segura-Collar, Berta; Gargini, Ricardo; Tovar-Ambel, Elena; Hernandez-Sanmiguel, Esther; Epifano, Carolina; Perez de Castro, Ignacio; Hernández-Laín, Aurelio; Casas-Tintó, Sergio; Sánchez-Gómez, Pilar; Ministerio de Economía y Competitividad (España); Asociación Española Contra el Cáncer
Despite the high frequency of EGFR and TP53 genetic alterations in gliomas, little is known about their crosstalk during tumor progression. Here, we described a mutually exclusive distribution between mutations in these two genes. We found that wild-type p53 gliomas are more aggressive than their mutant counterparts, probably because the former accumulate amplifications and/or mutations in EGFR and show a stronger activation of this receptor. In addition, we identified a series of genes associated with vesicular trafficking of EGFR in p53 wild-type gliomas. Among these genes, TMEM167A showed the strongest implication in overall survival in this group of tumors. In agreement with this observation, inhibition of TMEM167A expression impaired the subcutaneous and the intracranial growth of wild-type p53 gliomas, regardless of the presence of EGFR mutations. In the absence of p53 mutations, TMEM167A knockdown reduced the acidification of intracellular vesicles, affecting the autophagy process and impairing EGFR trafficking and signaling. This effect was mimicked by an inhibitor of the vacuolar ATPase. We propose that the increased aggressiveness of wild-type p53 gliomas might be due to the increase in growth factor signaling activity, which depends on the regulation of vesicular trafficking by TMEM167A.
Tumor-derived pericytes driven by EGFR mutations govern the vascular and immune microenvironment of gliomas.
(American Association for Cancer Research (AACR), 2021-02-16) Segura-Collar, Berta; Garranzo-Asensio, Maria; Herranz, Beatriz; Hernandez-Sanmiguel, Esther; Cejalvo, Teresa; Casas, Bárbara S; Matheu, Ander; Pérez-Núñez, Ángel; Sepúlveda-Sánchez, Juan Manuel; Hernández-Laín, Aurelio; Palma, Verónica; Gargini, Ricardo; Sánchez-Gómez, Pilar; Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española Contra el Cáncer; Ministerio de Ciencia, Innovación y Universidades (España)
The extraordinary plasticity of glioma cells allows them to contribute to different cellular compartments in tumor vessels, reinforcing the vascular architecture. It was recently revealed that targeting glioma-derived pericytes, which represent a big percentage of the mural cell population in aggressive tumors, increases the permeability of the vessels and improves the efficiency of chemotherapy. However, the molecular determinants of this transdifferentiation process have not been elucidated. Here we show that mutations in epidermal growth factor receptor (EGFR) stimulate the capacity of glioma cells to function as pericytes in a BMX (bone marrow and X-linked) and SOX9-dependent manner. Subsequent activation of platelet-derived growth factor receptor beta (PDGFRβ) in the vessel walls of EGFR mutant gliomas stabilized the vasculature and facilitated the recruitment of immune cells. These changes in the tumor microenvironment conferred a growth advantage to the tumors but also rendered them sensitive to pericyte-targeting molecules such as ibrutinib or sunitinib. In the absence of EGFR mutations, high-grade gliomas were enriched in blood vessels but showed a highly disrupted blood-brain-barrier due to the decreased BMX/SOX9 activation and pericyte coverage, which led to poor oxygenation, necrosis, and hypoxia. Overall, these findingds identify EGFR mutations as key regulators of the glioma-to-pericyte transdifferentiation, highlighting the intricate relationship between the tumor cells and their vascular and immune milieu. Our results lay the foundations for a vascular-dependent stratification of gliomas and suggest different therapeutic vulnerabilities determined by the genetic status of EGFR.
Blood-Brain Barrier Disruption: A Common Driver of Central Nervous System Diseases.
(SAGE Publishing, 2021-01-15) Segura-Collar, Berta; Mata-Martínez, Pablo; Hernández-Laín, Aurelio; Sánchez-Gómez, Pilar; Gargini, Ricardo; Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española Contra el Cáncer; Ministerio de Ciencia, Innovación y Universidades (España)
The brain is endowed with a unique cellular composition and organization, embedded within a vascular network and isolated from the circulating blood by a specialized frontier, the so-called blood-brain barrier (BBB), which is necessary for its proper function. Recent reports have shown that increments in the permeability of the blood vessels facilitates the entry of toxic components and immune cells to the brain parenchyma and alters the phenotype of the supporting astrocytes. All of these might contribute to the progression of different pathologies such as brain cancers or neurodegenerative diseases. Although it is well known that BBB breakdown occurs due to pericyte malfunctioning or to the lack of stability of the blood vessels, its participation in the diverse neural diseases needs further elucidation. This review summarizes what it is known about BBB structure and function and how its instability might trigger or promote neuronal degeneration and glioma progression, with a special focus on the role of pericytes as key modulators of the vasculature. Moreover, we will discuss some recent reports that highlights the participation of the BBB alterations in glioma growth. This pan-disease analysis might shed some light into these otherwise untreatable diseases and help to design better therapeutic approaches.
Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators
(BioMed Central (BMC), 2023-05-10) Segura-Collar, Berta; Hiller-Vallina, Sara; Dios Huerta, Olaya de; Caamaño-Moreno, Marta; Mondejar-Ruescas, Lucia; Sepulveda-Sanchez, Juan M; Gargini, Ricardo; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Asociación Española Contra el Cáncer; Ministerio de Ciencia e Innovación (España)
Glial-origin brain tumors, including glioblastomas (GBM), have one of the worst prognoses due to their rapid and fatal progression. From an oncological point of view, advances in complete surgical resection fail to eliminate the entire tumor and the remaining cells allow a rapid recurrence, which does not respond to traditional therapeutic treatments. Here, we have reviewed new immunotherapy strategies in association with the knowledge of the immune micro-environment. To understand the best lines for the future, we address the advances in the design of neoantigen vaccines and possible new immune modulators. Recently, the efficacy and availability of vaccine development with different formulations, especially liposome plus mRNA vaccines, has been observed. We believe that the application of new strategies used with mRNA vaccines in combination with personalized medicine (guided by different omic's strategies) could give good results in glioma therapy. In addition, a large part of the possible advances in new immunotherapy strategies focused on GBM may be key improving current therapies of immune checkpoint inhibitors (ICI), given the fact that this type of tumor has been highly refractory to ICI.
On optimal temozolomide scheduling for slowly growing glioblastomas
(Oxford University Press, 2022-09) Segura-Collar, Berta; Jiménez-Sánchez, Juan; Gargini, Ricardo; Dragoj, Miodrag; Sepúlveda-Sánchez, Juan M; Pešić, Milica; Ramírez-González, María A; Ayala-Hernández, Luis E; Sánchez-Gómez, Pilar; Pérez-García, Víctor M; James S. McDonnell Foundation; Ministry of Education, Science and Technological Development (Serbia); Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III; University of Castilla-La Mancha (España)
Background: Temozolomide (TMZ) is an oral alkylating agent active against gliomas with a favorable toxicity profile. It is part of the standard of care in the management of glioblastoma (GBM), and is commonly used in low-grade gliomas (LGG). In-silico mathematical models can potentially be used to personalize treatments and to accelerate the discovery of optimal drug delivery schemes. Methods: Agent-based mathematical models fed with either mouse or patient data were developed for the in-silico studies. The experimental test beds used to confirm the results were: mouse glioma models obtained by retroviral expression of EGFR-wt/EGFR-vIII in primary progenitors from p16/p19 ko mice and grown in-vitro and in-vivo in orthotopic allografts, and human GBM U251 cells immobilized in alginate microfibers. The patient data used to parametrize the model were obtained from the TCGA/TCIA databases and the TOG clinical study. Results: Slow-growth "virtual" murine GBMs benefited from increasing TMZ dose separation in-silico. In line with the simulation results, improved survival, reduced toxicity, lower expression of resistance factors, and reduction of the tumor mesenchymal component were observed in experimental models subject to long-cycle treatment, particularly in slowly growing tumors. Tissue analysis after long-cycle TMZ treatments revealed epigenetically driven changes in tumor phenotype, which could explain the reduction in GBM growth speed. In-silico trials provided support for implementation methods in human patients. Conclusions: In-silico simulations, in-vitro and in-vivo studies show that TMZ administration schedules with increased time between doses may reduce toxicity, delay the appearance of resistances and lead to survival benefits mediated by changes in the tumor phenotype in slowly-growing GBMs.
Ammonia Affects Astroglial Proliferation in Culture
(Public Library of Science (PLOS), 2015-09-30) Bodega, Guillermo; Segura-Collar, Berta; Ciordia, Sergio; Mena, María Del Carmen; López-Fernández, Luis Andrés; García, María Isabel; Trabado, Isabel; Suárez, Isabel; University of Alcalá (España)
Primary cultures of rat astroglial cells were exposed to 1, 3 and 5 mM NH4Cl for up to 10 days. Dose- and time-dependent reductions in cell numbers were seen, plus an increase in the proportion of cells in the S phase. The DNA content was reduced in the treated cells, and BrdU incorporation diminished. However, neither ammonia nor ammonia plus glutamine had any effect on DNA polymerase activity. iTRAQ analysis showed that exposure to ammonia induced a significant reduction in histone and heterochromatin protein 1 expression. A reduction in cell viability was also noted. The ammonia-induced reduction of proliferative activity in these cultured astroglial cells seems to be due to a delay in the completion of the S phase provoked by the inhibition of chromatin protein synthesis.
Novel Functions of the Neurodegenerative-Related Gene Tau in Cancer
(Frontiers Media, 2019) Gargini, Ricardo; Segura-Collar, Berta; Sánchez-Gómez, Pilar; Asociación Española Contra el Cáncer; Ministerio de Economía y Competitividad (España)
The analysis of global and comparative genomics between different diseases allows us to understand the key biological processes that explain the etiology of these pathologies. We have used this type of approach to evaluate the expression of several neurodegeneration-related genes on the development of tumors, particularly brain tumors of glial origin (gliomas), which are an aggressive and incurable type of cancer. We have observed that genes involved in Amyotrophic lateral sclerosis (ALS), as well as in Alzheimer's and Parkinson's diseases, correlate with better prognosis of gliomas. Within these genes, high Tau/MAPT expression shows the strongest correlation with several indicators of prolonged survival on glioma patients. Tau protein regulates microtubule stability and dynamics in neurons, although there have been reports of its expression in glial cells and also in gliomas. However, little is known about the regulation of Tau/MAPT transcription in tumors. Moreover, our in silico analysis indicates that this gene is also expressed in a variety of tumors, showing a general correlation with survival, although its function in cancer has not yet been addressed. Another remarkable aspect of Tau is its involvement in resistance to taxanes in various tumors types such as breast, ovarian and gastric carcinomas. This is due to the fact that taxanes have the same tubulin-binding site as Tau. In the present work we review the main knowledge about Tau function and expression in tumors, with a special focus on brain cancer. We will also speculate with the therapeutic implications of these findings.
Cellular Plasticity and Tumor Microenvironment in Gliomas: The Struggle to Hit a Moving Target.
(Multidisciplinary Digital Publishing Institute (MDPI), 2020-06-18) Gargini, Ricardo; Segura-Collar, Berta; Sánchez-Gómez, Pilar; Asociación Española Contra el Cáncer; Ministerio de Economía y Competitividad (España)
Brain tumors encompass a diverse group of neoplasias arising from different cell lineages. Tumors of glial origin have been the subject of intense research because of their rapid and fatal progression. From a clinical point of view, complete surgical resection of gliomas is highly difficult. Moreover, the remaining tumor cells are resistant to traditional therapies such as radio- or chemotherapy and tumors always recur. Here we have revised the new genetic and epigenetic classification of gliomas and the description of the different transcriptional subtypes. In order to understand the progression of the different gliomas we have focused on the interaction of the plastic tumor cells with their vasculature-rich microenvironment and with their distinct immune system. We believe that a comprehensive characterization of the glioma microenvironment will shed some light into why these tumors behave differently from other cancers. Furthermore, a novel classification of gliomas that could integrate the genetic background and the cellular ecosystems could have profound implications in the efficiency of current therapies as well as in the development of new treatments.
Oncogenic dependence of glioma cells on kish/TMEM167A regulation of vesicular trafficking
(Wiley, 2019) Portela, Marta; Segura-Collar, Berta; Argudo, Irene; Sáiz, Almudena; Gargini, Ricardo; Sánchez-Gómez, Pilar; Casas-Tintó, Sergio; Ministerio de Economía y Competitividad (España); Ministerio de Ciencia e Innovación (España); Asociación Española Contra el Cáncer
Genetic lesions in glioblastoma (GB) include constitutive activation of PI3K and EGFR pathways to drive cellular proliferation and tumor malignancy. An RNAi genetic screen, performed in Drosophila melanogaster to discover new modulators of GB development, identified a member of the secretory pathway: kish/TMEM167A. Downregulation of kish/TMEM167A impaired fly and human glioma formation and growth, with no effect on normal glia. Glioma cells increased the number of recycling endosomes, and reduced the number of lysosomes. In addition, EGFR vesicular localization was primed toward recycling in glioma cells. kish/TMEM167A downregulation in gliomas restored endosomal system to a physiological state and altered lysosomal function, fueling EGFR toward degradation by the proteasome. These endosomal effects mirrored the endo/lysosomal response of glioma cells to Brefeldin A (BFA), but not the Golgi disruption and the ER collapse, which are associated with the undesirable toxicity of BFA in other cancers. Our results suggest that glioma growth depends on modifications of the vesicle transport system, reliant on kish/TMEM167A. Noncanonical genes in GB could be a key for future therapeutic strategies targeting EGFR-dependent gliomas.