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.

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

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

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

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

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.

The effect of targeted cancer therapies on non-small cell lung cancer brain metastases, crossing the blood-brain barrier

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

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

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

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

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

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

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

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

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

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

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

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

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

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.