Our publications reflect our interests in the fields of Cancer Biology and Neuroscience. This allows us to study brain metastases using a variety of techniques. Here are our most significant contributions to both disciplines.

Brain metastases cell partners and tumor microenvironment

García-Gómez, Priego, Álvaro-Espinosa, Valiente M. Springer. (2020)

In this book chapter we provide a broad overview of the crosstalk between metastasis and the brain microenvironment. The chapter is part of the first monographic book about Central Nervous System metastasis.

Brain metastasis

Boire, Brastianos, Garzia and Valiente. Nat Rev Cancer. (2019)

In this viewpoint article we give our opinion about several important aspects related to the biology and clinical implications of brain metastasis. Together with the other three co-authors, all leaders in the brain metastasis field, the article gives an up to date vision of the current situation and suggests various emerging areas of research.

This work is part of a full issue dedicated to brain tumors:

The Potential of Astrocytes as Immune Modulators in Brain Tumors

Priego and Valiente. Front. Immunol. (2019)

In this review article we discuss about the limited attention that has been put on astrocytes as cells with the ability to influence the immune system locally in the context of brain tumors. We compare astrocytes in brain tumors and other disorders affecting the CNS since there are important similarities but also differences that might interesting to explore.

Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis

Wingrove et al. Cell Reports. (2019)

We collaborated with Don Nguyen (Yale) to develop and improved strategy to analyze xenografts directly from tissue and probed its value to define new potential mediators of brain metastasis. In addition, a friendly web interface (BMX-seq Explorer was created to explore this data.

Vascular co-option in brain metastasis

García-Gómez and Valiente. Angiogenesis. (2019)

The ability of cancer cells to maintain a perivascular location during organ colonization seems to be a hallmark of metastasis, especially during the early stages. We discuss the still limited knowledge about this process and the implications that have been noticed.

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

Priego et al. Nat Med. (2018)

Once metastatic cells start to grow in the brain they change the microenvironment. We have found that some of these modifications reprogram cell types from the brain and turn them into pro-metastatic components. In fact, when we block one of such altered molecular patterns we found in reactive astrocytes, we realized we were able to impair brain metastases even at advanced stages of local colonization. Blockade of STAT3 in reactive astrocytes using pharmacologic approaches was a successful strategy in both experimental models and patients affected with brain metastasis. We report the fascinating biology of this subpopulation of reactive astrocytes associated with brain metastasis as modulators of local immunity.

Silibinin is a direct inhibitor of STAT3

Verdura et al. Food Chem Toxicol. (2018)

This study was a collaboration by which we probed that silibinin is a direct STAT3 inhibitor using a variety of bioinformatic, structural and biochemical approaches.

Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization

Er et al. Nat Cell Biol. (2018)

L1CAM is a key molecule mediating vascular co-option, which is a critical mechanism to initiate metastasis in multiple organs. Our findings include the validation of a conserved mechanism to inhabit the perivascular niche in a variety of highly prevalent cancer types. This molecular mechanism that mimics the ability of pericytes to interact with the vasculature might give rise to novel strategies to prevent the development of metastases.

The evolving landscape of brain metastasis

Valiente et al. Trends in Cancer. (2018)

Although brain metastasis is associated with high morbility and mortality there have been important findings in recent years that allow to be moderately optimistic about the coming future. We reviewed these aspects within a group of experts with different backgrounds including basic scientists and clinicians identifying which are the most promising opportunities to move forward.

Recent advances in the biology and treatment of brain metastases of non- small cell lung cancer: summary of a multidisciplinary roundtable discussion

Preusser et al. ESMO Open. (2018)

This article is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose is to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non- small cell lung cancer.

Reactive Astrocytes in Brain Metastasis

Wasilewski et al. Front Oncol. (2017)

We review the current knowledge regarding the involvement of the microenvironment in brain metastasis with a special focus on astrocytes. Given the significant knowledge accumulated over the years suggesting the important role of this cell type at different stages during brain colonization by cancer cells, we have generated the first bibliographic revision on this exciting topic.

T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression

Mustafa et al. Acta Neuropathol. (2018)

In collaboration with the group of Dr. Kros (Erasmus MC, Holland) we have found that enrichment of T lymphocytes in the primary tumor of ER- breast cancer patients correlates with an increased incidence of brain metastasis. This surprising finding involves the interaction between cancer cells and T cells at the primary tumor. This communication between different cell types prime cancer cells to get access to the brain by facilitating their ability to cross the blood-brain barrier.

Neuregulin 3 Mediates Cortical Plate Invasion and Laminar Allocation of GABAergic Interneurons

Bartolini et al. Cell Reports. (2017)

Neural circuits in the cerebral cortex consist of excitatory pyramidal cells and inhibitory interneurons. These two main classes of cortical neurons follow largely different genetic programs, yet they assemble into highly specialized circuits during development following a very precise choreography. We have collaborated in the identification of Neuregulin 3 (Nrg3) as a chemoattractive factor guiding the allocation of cortical interneurons. Nrg3 is therefore a critical mediator in the assembly of cortical inhibitory circuits.

Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer

Chen et al. Nature. (2017)

The interactions with the microenvironment are critical during the process of metastasis. In this work, in which the lab has participated as a collaborator, we report that the few cancer cells surviving after the initial steps of brain colonization establish gap junctions with glial cells. These interactions provide cancer cells with an increased ability to grow in the brain and, more importantly, to resist drugs. Blocking this mechanism turns brain metastasis sensitive to chemotherapy.

Loss of the multifunctional RNA-binding protein RBM47 as a source of selectable metastatic traits in breast cancer

Vanharanta et al. eLife. (2014)

RNA-binding proteins are starting to be characterized functionally. We report here one of the first cases of this kind of molecules being involved in the metastatic process of renal cancer, including metastasis affecting the brain.

Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis

Valiente et al. Cell. (2014)

This publication has been considered a landmark paper (Comments on: – Nature – EMBO – Cancer Discov. – Sci. Signal – Nat. Rev. Clin. Oncol. – Nat. Cell Biol. – N. Engl. J. Med) in the field considering the novel technical approaches that it presents and critical discoveries of the biology of brain metastasis. We report how brain metastatic cells are protected against the reactive microenvironment which is in fact responsible for the high inefficiency of metastatic disease in the brain. This mechanism is required to allow metastatic cells co-opt the vasculature, a critical requirement to colonize the brain.

Focal Adhesion Kinase modulates radial glia-dependent neuronal migration through Connexin-26

Valiente et al. J Neurosci. (2011)

By using genetically modified mouse models, in utero electroporation and in vivo virus infection we characterized the role of this kinase in the migration of the neuronal precursors in the brain. We described the interaction between FAK and GAP junction proteins to allow the correct interaction with the “scaffold” represented by the radial glia. Interestingly the migration of interneurons, which is independent of the radial glia, it does not require FAK either.

Neuronal migration mechanisms in development and disease

Valiente and Marín. Curr Opin Neurobiol. (2010)

A comprehensive review of neuronal migration including links to neurological syndromes. It summarizes both the advances in the understanding of the cellular biology during different migratory patterns as well as the discoveries in their molecular regulation.

Guiding Neuronal Cell Migrations

Marín et al. Cold Spring Harb Perspect Biol. (2010)

As part of a book chapter, we review together with main leaders in Neurobiology the state-of-the-art in axon guidance and migration. Our review and book chapter is focused on migrations of neuronal precursors.

Ikaros-1 couples cell cycle arrest of late striatal precursors with neurogenesis of enkephalinergic neurons

Martín-Ibáñez et al. J Comp Neurol. (2010)

Neuronal differentiation is key to obtain the functional diversity present in the complex brain circuitry. In this paper the transcription factor Ikaros-1 is identified as a critical mechanism to differentiate a subpopulation of striatal interneurons.

Control of cortical GABA circuitry development by Nrg1 and ErbB4

Fazzari et al. Nature. (2010)

This article is a clear demonstration of the relationship between neuropsychiatric disorders and development. Signaling pathway NRG-1/ ErbB4 is critical for migration of neural precursors and correct terminal differentiation of interneurons. Loss of ErbB4 function in interneurons during embryonic development causes the appearance of electrophysiological and behavioral deficits in the adult highly linked to schizophrenia.

Biased selection of leading process branches mediates chemotaxis during tangential neuronal migration

Martini, Valiente et al. Development. (2009)

By using time-lapse video-microscopy in organotypic cultures we characterized the migratory behavior of cortical interneurons. We specifically define how the bifurcated leading edge is the most efficient adaptation for the migratory pathway of these cells.

Migration of cortical interneurons relies on branched leading processes dynamics

Valiente and Martini. Cell Adhesion & Migration. (2009)

In this review I discussed the involvement of developing a branched leading process during migration. The broad co-option of this migratory behavior among different neuronal precursors suggests an improved navigation pattern.