Metastatic breast cancer cells induce altered microglial morphology and electrical excitability in vivo

• Published in: Journal of neuroinflammation 2020-03, Vol.17 (1), p.87-87, Article 87
• Main Authors: Simon, Anna, Yang, Ming, Marrison, Joanne L, James, Andrew D, Hunt, Mark J, O'Toole, Peter J, Kaye, Paul M, Whittington, Miles A, Chawla, Sangeeta, Brackenbury, William J
• Format: Article
• Language: English
• Subjects: Animals; Brain; Brain cancer; Brain Neoplasms - secondary; Brain tumors; Breast cancer; Breast Neoplasms - pathology; Cancer cells; Cancer metastasis; Cancer treatment; Cell Line, Tumor; Cytology; Development and progression; Disease Models, Animal; Electrophysiology; Excitability; Female; Health aspects; Inflammation; Intravital imaging; Intravital Microscopy - methods; Macrophages; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Morphology; Neural circuitry; Neurons; Physiological aspects; Population; Seizures (Medicine); Surgery; Tumor Microenvironment - physiology; Tumors
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-020-01753-0

An emerging problem in the treatment of breast cancer is the increasing incidence of metastases to the brain. Metastatic brain tumours are incurable and can cause epileptic seizures and cognitive impairment, so better understanding of this niche, and the cellular mechanisms, is urgently required. Microglia are the resident brain macrophage population, becoming "activated" by neuronal injury, eliciting an inflammatory response. Microglia promote proliferation, angiogenesis and invasion in brain tumours and metastases. However, the mechanisms underlying microglial involvement appear complex and better models are required to improve understanding of function. Here, we sought to address this need by developing a model to study metastatic breast cancer cell-microglial interactions using intravital imaging combined with ex vivo electrophysiology. We implanted an optical window on the parietal bone to facilitate observation of cellular behaviour in situ in the outer cortex of heterozygous Cx3cr1 mice. We detected GFP-expressing microglia in Cx3cr1 mice up to 350 μm below the window without significant loss of resolution. When DsRed-expressing metastatic MDA-MB-231 breast cancer cells were implanted in Matrigel under the optical window, significant accumulation of activated microglia around invading tumour cells could be observed. This inflammatory response resulted in significant cortical disorganisation and aberrant spontaneously-occurring local field potential spike events around the metastatic site. These data suggest that peritumoral microglial activation and accumulation may play a critical role in local tissue changes underpinning aberrant cortical activity, which offers a possible mechanism for the disrupted cognitive performance and seizures seen in patients with metastatic breast cancer.