Abstract 4307: Quantifying the cell-intrinsic and cell-extrinsic growth effects of cancer-causing mutations in vivo

Abstract

Abstract Adaptive driver phenotypes in cancer must confer either a cell-intrinsic (birth minus death) or cell-extrinsic (field) effect on growth. These effects can be summarized by an r/K logistic growth curve, whereby cell-intrinsic effects manifest as a change in the early, exponential growth constant (r) of a tumor population while cell-extrinsic effects alter the long-term ‘carrying capacity’ (K). Previously, we developed a novel genetically-engineered mouse model that tracks tumor growth dynamics with unprecedented precision via Tumor Barcoding, termed TuBa-seq1. Here, we quantify the growth trajectories of thousands of Kras-driven lung tumors over eight months. Median tumor size is best-described by a Gomp-Ex growth law (i.e. Nν/K where ν → +0), which also characterizes advanced-stage human tumors2. Carrying capacities of individual isogenic tumors varied by over four orders of magnitude, suggesting that microenvironmental heterogeneity profoundly impacts growth dynamics. Our approach further allowed us to track the growth effects of eleven canonical tumor suppressor gene knockouts introduced via multiplexed CRISPR/Cas genome-engineering. All but one of these secondary mutations augmented either the exponential growth rate or the carrying capacity of the tumor. However, only three tumor suppressor losses increased both growth parameters (Rb1, Setd2, and Stk11). Hence, the growth benefits of most cancer-causing mutations are missed when growth is measured only at a single time point. Clinically, we find that r-promoting and K-promoting mutations interact synergistically to create the most aggressive tumors in human patients (HR = 1.71, P-value < 10-10). Collectively, these results support a universal r/K framework for tumor growth and progression.