Journal
ADVANCED SCIENCE
Volume 6, Issue 8, Pages -Publisher
WILEY
DOI: 10.1002/advs.201801531
Keywords
brain tumor dynamics; ex vivo assays; microvasculature; organ-on-a-chip
Categories
Funding
- Packard Fellowship for Science and Engineering
- National Science Foundation CAREER Award [CBET-1351443]
- National Cancer Institute [U54 CA193461, U54 CA209992, 7297]
- National Institutes of Health [R01 NS095817]
- Yale Cancer Center Co-Pilot Grant
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The perivascular niche (PVN) plays an essential role in brain tumor stem-like cell (BTSC) fate control, tumor invasion, and therapeutic resistance. Here, a microvasculature-on-a-chip system as a PVN model is used to evaluate the ex vivo dynamics of BTSCs from ten glioblastoma patients. BTSCs are found to preferentially localize in the perivascular zone, where they exhibit either the lowest motility, as in quiescent cells, or the highest motility, as in the invasive phenotype, with migration over long distance. These results indicate that PVN is a niche for BTSCs, while the microvascular tracks may serve as a path for tumor cell migration. The degree of colocalization between tumor cells and microvessels varies significantly across patients. To validate these results, single-cell transcriptome sequencing (10 patients and 21 750 single cells in total) is performed to identify tumor cell subtypes. The colocalization coefficient is found to positively correlate with proneural (stem-like) or mesenchymal (invasive) but not classical (proliferative) tumor cells. Furthermore, a gene signature profile including PDGFRA correlates strongly with the homing of tumor cells to the PVN. These findings demonstrate that the model can recapitulate in vivo tumor cell dynamics and heterogeneity, representing a new route to study patient-specific tumor cell functions.
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