Decoding Brain Cancer Ecosystem in Humans: From Complexity to Mechanism

Toshiro Hara

Assistant Professor

University of Michigan, Medical School

Abstract:

Glioblastoma is an incurable form of brain tumor. It is a community of diverse tumor cells that share brain space for their growth and invasion, engaging in a variety of cellular communications, from tumor-immune interactions to tumor-brain structure interactions. Understanding the intricacies might help us to urge improvements in therapies and outcomes for patients. We characterized human tumors and model systems by single-cell expression profiling and spatial analysis and found that glioblastoma is dominated by a limited set of four tumor subpopulations. Our subsequent work to dissect glioblastoma-microenvironment interactions revealed that macrophages are the major immune infiltrate and induce mesenchymal phenotypes, one of the four states, in glioblastoma cells. Further, we experimentally demonstrated that the mesenchymal state in glioblastoma is associated with cytotoxic T-cell programs. As a tool for probing the function and dynamics of tumor subpopulations, we adapted patient-derived xenografts (PDX) for pooling in multiplexed assays and examined the geographically diffusive nature of glioblastoma at the single-cell level. With models capable of invading along the periphery of neurons or blood vessels, our analysis revealed the ability of glioblastoma cells to change their phenotypes in response to environmental changes. Collectively, our studies lead to new insights into the effect of cell-cell interactions on intratumoral heterogeneity and response to therapies.

References:

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