The maintenance of multiple ecDNA types in single cancer cells

Abstract

Extrachromosomal DNA (ecDNA) emerges as a crucial promoter of rapid intra-tumour heterogeneity and oncogene amplification, contributing to tumour progression and adaptability to resistance. Multiple types of ecDNA are often observed within the same cancer cell, promoting high levels of complexity. While the study of multiple ecDNA types is still in its early stages with exciting new clinical and experimental studies in human cancers, few theoretical models have been proposed to understand the mechanisms enabling the maintenance of multiple ecDNA types (mix cells). Here, based on our general framework of modeling multiple ecDNA types, we explore the conditions that allow for a stable coexistence of multiple ecDNA types within single cancer cells. We study how genetic mutations or phenotypic switching among different ecDNA types contribute to the maintenance of ecDNA diversity under different fitness regimes. We show that either positive epistasis or switching is required to stably maintain mix cell populations. Counter-intuitively, intermediate rather than high switching rates lead to the highest fraction of mix cells, which is further confirmed by our analysis of sub-population compositions, transition probabilities between pure and mix states as well as single-cell Shannon indices.