Integrative and Quantitative Analysis of Tumor Progression Reveals Fundamental Properties of Glioblastoma

Principle of tumor growth is one fundamental aspect of cancer biology and it remains to be superficially understood. Here we developed a set of genetic and mathematic tools allow integrative analysis of mouse glioblastoma (GBM) progression. Quantitative temporal imaging of mouse GBM and mathematic modeling suggest that mouse GBM grows exponentially, which led to the discovery that a sustainable exponential growth requires outward migrating brain tumor stem cells (BTSCs). Quantitative single cell tracing of BTSCs in vivo unravels symmetric expansion of BTSCs, asymmetric differentiation, and a non-reversible differentiation process during tumor progression. Mosaic tracing of BTSCs and non-BTSCs reveals a cellular temporal dynamic changes and cellular turnover. These experimentally collected parameters were integrated step by step to a quantitative mathematic model of GBM growth, which faithfully predicts tumor cellular architecture, tumor response to chemotherapy and BTSC therapy. Bulk and single cell RNA-Seq reveals distinct molecular hierarchy and molecular heterogeneity in BTSCs, which was confirmed by analyzing human GBM single cell RNA-Seq results. This study reveals basic developmental principles that govern tumor development, which provides novel understanding of cancer development, tumor heterogeneity and new approaches to treat GBM.