Abstract B041: Inferring subclonal fitness landscapes from single-cell tumor phylogenies

Abstract Subclones within a patient tumor can differ in their growth rates within the tumor microenvironment. Characterizing this intra-tumor-heterogeneity (ITH) in growth rates offer insights into the tumor’s evolutionary trajectories and the specific aberrations that underpin adaptive success. Recent advancement in single cell sequencing technique provides enhanced resolution in genomic architecture. We developed ith.Fitness, a mathematical framework that leverages the topology of reconstructed single cell phylogenetic trees to infer the relative fitness of individual cells at the leaves and quantify growth-rate variation among subclones. In contrast to existing evolutionary fitness ranking tools originally designed for pathogens such as influenza, our method assumes an evolutionary scenario characterized by potentially large fitness effects from rare driver aberrations and expanding population, more closely reflecting the dynamics of cancer evolution. In addition, ith.Fitness incorporates a tree-rescaling strategy to adjust for variable mutation rates along specific branches, such as those following the event of whole genome doubling (WGD). Simulation demonstrates the accuracy of our method in both non-spatial and spatial tumor growth models. Applied to single cell whole-genome-sequencing data from ovarian cancer, ith.Fitness identified both slow-cycling and fast-growing subclones. Interestingly, subclones arising with WGD do not show elevated growth rates relative to sibling lineages without WGD at the time of sampling. However, WGD-positive cells may gain fitness advantages over time and ultimately dominate tumor evolution. Citation Format: Ruping Sun, Chenyu Wu, Zicheng Wang. Inferring subclonal fitness landscapes from single-cell tumor phylogenies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B041.