The brain microenvironment as a target of effective anti-metastasis strategies in mice and human

2020/01/23 Atrio 800

Seminar

The brain microenvironment as a target of effective anti-metastasis strategies in mice and human

Manuel Valiente, PhD

The brain microenvironment as a target of effective anti-metastasis strategies in mice and human 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, which eliminates the vast majority of recently extravasated cancer cells, is slowly reprogrammed into a strong pro-tumor niche. 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. We recently 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 effectiveness of a pharmacological strategy targeting this altered molecular pattern in mice and human affected by brain metastasis suggests that current systemic approaches could be significantly improved by incorporating drugs targeting the microenvironment. Relevant publications 1. Boire A*, Brastianos P*, Garzia L*, Valiente M*. Viewpoint: Brain Metastasis. Nat Rev Cancer. DOI: 10.1038/s41568-019-0220-y (*) Co-corresponding author. 2. Priego N, et al., Valiente M*. (2018) STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nature Medicine. 24(7):1024-1035. (*) Corresponding author. Comments on: Nat. Medicine, Trends Mol Med., Nat Rev Cancer, Nat Rev Neurol. 3. Er E, Valiente M*, Ganesh K* et al. Pericyte-Like Spreading by Disseminated Cancer Cells Activates YAP and MRTF for Metastatic Colonization. Nature Cell Biology. 20(8):966-9784. (*) Shared authorship. Comments on: Nat Cell Biol., F1000 Prime evaluation. 4. Valiente M*, et al., Soffietti R*. (2018). The evolving landscape of brain metastasis. Trends in Cancer. 4(3):176-196. (*) Co-corresponding author. Comments on: Review of the year by Trends in Cancer. 5. Chen Q*, Boire A*, Jin X, Valiente M, et al. (2016) Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature. 533:493-498. (*) Shared authorship. This work generated a clinical trial (NCT02429570). Comments on: Cell Res., F1000 Prime evaluation, Nat Rev Cancer, Cancer Discov., Neurosurgery. 6. Valiente M, et al. (2014) Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 156:1002-1016. Comments on: Nature, EMBO J., Cancer Discov., Sci. Signal., Nat. Rev. Clin. Oncol., Nat. Cell Biol., N. Engl. J. Med.

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