STAT3-mediated astrocyte reactivity associated with brain metastasis contributes to neurovascular dysfunction

Sarmiento Soto, Manuel; Larkin, James R.; Martin, Chris; Khrapitchev, Alexandre A.; Maczka, Melissa; Economopoulos, Vasiliki; Scott, Helen; Escartin, Carole; Bonvento, Gilles; Serres, S�bastien; Sibson, Nicola R.

Abstract

© 2020 American Association for Cancer Research. Astrocytes are thought to play a pivotal role in coupling neural activity and cerebral blood flow. However, it has been shown that astrocytes undergo morphologic changes in response to brain metastasis, switching to a reactive phenotype, which has the potential to significantly compromise cerebrovascular function and contribute to the neurological sequelae associated with brain metastasis. Given that STAT3 is a key regulator of astrocyte reactivity, we aimed here to determine the impact of STAT3- mediated astrocyte reactivity on neurovascular function in brain metastasis. Rat models of brain metastasis and ciliary neurotrophic factor were used to induce astrocyte reactivity. Multimodal imaging, electrophysiology, and IHC were performed to determine the relationship between reactive astrocytes and changes in the cerebrovascular response to electrical and physiological stimuli. Subsequently, the STAT3 pathway in astrocytes was inhibited with WP1066 to determine the role of STAT3- mediated astrocyte reactivity, specifically, in brain metastasis. Astrocyte reactivity associated with brain metastases impaired cerebrovascular responses to stimuli at both the cellular and functional level and disrupted astrocyte-endothelial interactions in both animal models and human brain metastasis samples. Inhibition of STAT3-mediated astrocyte reactivity in rats with brain metastases restored cerebrovascular function, as shown by in vivo imaging, and limited cerebrovascular changes associated with tumor growth. Together these findings suggest that inhibiting STAT3-mediated astrocyte reactivity may confer significant improvements in neurological outcome for patients with brain metastases and could potentially be tested in other brain tumors.

• Journal Article Type: Article
• Acceptance Date: Oct 21, 2020
• Online Publication Date: Oct 26, 2020
• Publication Date: Dec 15, 2020
• Deposit Date: Oct 30, 2020
• Publicly Available Date: Oct 27, 2021
• Journal: Cancer Research
• Print ISSN: 0008-5472
• Electronic ISSN: 1538-7445
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 80
• Issue: 24
• Pages: 5642-5655
• DOI: https://doi.org/10.1158/0008-5472.CAN-20-2251
• Keywords: Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/5008747
• Publisher URL: https://cancerres.aacrjournals.org/content/early/2020/10/24/0008-5472.CAN-20-2251