Phylogenetic and phylodynamic approaches to understanding the evolution of non-small cell lung cancer using single-cell sequencing

Abstract Characterizing the genealogy of tumor cells and their population dynamics is central to our understanding of the evolution of cancer. While direct monitoring of the tumor evolutionary process is impractical, we leverage advances in phylogenetics and phylodynamics to explore the evolutionary dynamics of non-small cell lung cancer (NSCLC) using single-cell whole exome sequencing data from 351 tumor cells across 11 NSCLC patients, predominantly focusing on the primary tumors and early stages of NSCLC. Our results reveal distinct phylogenetic tree shapes and evolutionary trajectories across different stages of NSCLC evolution. However, this intricate and multi-phase evolutionary process cannot be fully elucidated by current tumor models. Herein, we hypothesize that tumors progress through the following phases: (1) an initial rapid expansion through Big Bang-like growth, (2) a prolonged plateau period of non-progression with possible accumulation of neutral substitutions, (3) a subsequent phase where adaptive substitutions accumulate gradually, (4) a bottleneck event where selectively advantageous subclones acquire invasive capabilities (characterized by a pattern of punctuated evolution), and, potentially, a rapid expansion leading to metastasis. This work highlights the use of single-cell phylogenetics and phylodynamics for interpreting the evolution of NSCLC, with potential in predicting cancer progression, resistance mechanisms, and treatment response.