Nested ecosystems theory for conceptualizing brain tumors

The application of advanced multi-omic methodologies to studying brain tumors has culminated in the appreciation that these cancers function as ecosystems that depend on the interactions of a diverse collection of cell types and signals. This connectivity operates not only at the level of the cancer cell, in which variants create new growth dependencies, but also between tumor cells and the immediate tumor microenvironment, between tumor cells and cell populations residing elsewhere in the brain tissue or body, and in response to extracorporeal factors. The cellular and molecular relationships within these four interrelated strata (intracellular, extracellular, intracorporeal and extracorporeal) act in concert to dictate brain tumor development, progression, and therapeutic response by creating biological heterogeneity and unique growth dependencies. In this Perspective, we apply the concept of nested ecosystems to the most common brain tumor (glioma), providing a contextual framework to define how risk factors modify central nervous system oncobiology and to identify future targeted approaches to disease mitigation.