Evolutionary and spatial dynamics underlying intra-tumor heterogeneity

Abstract

Intra-tumor heterogeneity (ITH) is a pervasive feature of solid tumors that complicates clinical prognosis and management. Yet, the evolutionary processes that explain ITH remain largely unresolved. Here, we demonstrate that phylodynamic models can provide valuable insight into these dynamics from multi-region sequencing data of resected tumors. We introduce a novel state-dependent birth-death and sequence evolution model that detects signals of boundary-driven growth in hepatocellular carcinoma. We further adapt a continuous trait evolution model to reconstruct joint spatial and genetic diversification in prostate cancer. Finally, we tackle the fundamental question of heritable versus non-heritable determinants of transcriptomic variability in prostate cancer and find unique genetic contributions to key cancer-related processes.