Seminario de Investigación: The biology of brain colonization by metastatic cells.

Manuel Valiente, Centro Nacional de Investigaciones Oncológicas -CNIO, Madrid

Resumen: Existing evidences at the cellular, clinical and genomic levels suggest that brain metastases differ from their corresponding primary tumor. One reason that could underlie this divergent evolution might derive from the unique brain microenvironment. An initial anti-metastatic naïve brain environment that eliminates the vast majority of recently extravasated cancer cells is slowly reprogrammed into a strong pro-tumor niche that finally supports the growth of the limited cells that survived. This switch from an anti-tumor to a pro-tumor brain microenvironment correlates with the emergence of altered molecular patterns affecting specific resident cell types. Specifically, we identified the activation of STAT3 pathway in reactive astrocytes surrounding brain metastasis. Genetic strategies demonstrated that this reprogrammed component of the microenvironment, which is not present in a normal brain, is responsible for establishing a potent immunomodulatory program that sustains the growth of brain metastasis through a network that involves macrophages and T cells. The unprecedented success of a pharmacological strategy targeting this altered molecular pattern in reactive astrocytes from both mice and humans with brain metastasis suggests that current systemic approaches could be significantly improved by incorporating additional drugs targeting the microenvironment.

Bio: Manuel Valiente (Zaragoza, 1980) has a degree in Veterinary Medicine (1998-2003, Zaragoza) awarded with the Extraordinary Degree Award and the second National Award in Veterinary Medicine. His interest in the Central Nervous System led him to earn a doctorate in Neuroscience (Instituto de Neurociencias, Alicante, 2009). In the laboratory of Oscar Marín he developed several projects to understand the principles that govern migration of neuronal precursors that later establish neuronal circuits in the cerebral cortex. His doctoral work produced eight publications in leading journals in the field and received the Extraordinary Doctoral Award. Later on, Manuel joined the laboratory of Joan Massagué (Memorial Sloan Kettering Cancer Center, New York, 2010) where he started to work on brain metastasis discovering critical mechanisms during the colonization of this organ that have been translated in several publications, patents and generated a clinical trial. Manuel established the Brain Metastasis Group at CNIO in 2015, where he leads a team of scientists whose goal is to discover critical aspects of the biology of brain metastasis in order to develop new therapeutic opportunities. His group has pioneered novel strategies to target molecular alterations within the brain metastasis microenvironment that have been proved to be potent anti-metastatic approaches in experimental models and patients. During this period Manuel has received several awards for his scientific contributions, including the EMBO YIP, and attracted competitive grants such as the ERC CoG.

Most relevant publications

1. Priego N, Zhu L, Monteiro C, Mulders M, Wasilewski D, Bindeman W, Doglio L, Martínez L, Martínez-Saez E, Ramón y Cajal S, Megías D, Hernández-Encinas E, Blanco-Aparicio C, Martínez L, Zarzuela E, Muñoz J, Fustero-Torres C, Pineiro E, Hernández-Laín A, Bertero L, Poli V, Sánchez-Martínez M, Menendez JA, Soffietti R, Bosch-Barrera J, Valiente M*. (2018) STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nature Medicine. DOI 10.1038/s41591-018-0044-4. (*) Corresponding author.

2. Er E, Valiente M*, Ganesh K*, Zou Y, Agrawal S, Griscom B, Giancotti F, Schachner M, Malladi S, Massagué J. Pericyte-Like Spreading by Disseminated Cancer Cells Activates YAP and MRTF for Metastatic Colonization. Nature Cell Biology. 20(8):966-9784. (*) Shared authorship.

3. Valiente M*, Lee EQ, Ahluwalia M, Brastianos PK, Preusser M, Goldberg S, Winkler F, Le Rhun E, Boire A, Soffietti R*. (2018). The evolving landscape of brain metastasis. Trends in Cancer. 4(3):176-196. (*) Co-corresponding author.

Fecha y hora: Viernes, 20 de diciembre de 2019. 12:30 h.

Lugar: Seminario IV