Unscheduled polyploidy synergizes with oncogenic mutations to enhance genome instability and tumorigenesis.

Polyploid Giant Cancer Cells (PGCCs) occur across multiple cancer types and are associated with therapy resistance, genome instability, disease progression, and metastasis. PGCCs can grow through endocycles, a variant cell cycle of alternating Growth (G) and DNA Synthesis (S) phases without cell division. Unlike programmed endocycles that occur during normal tissue development, PGCCs switch from mitotic cycles to unscheduled endocycles in response to stress. PGCCs can subsequently return to error-prone divisions which generate aneuploid daughter cells that contribute to disease progression. However, the regulation of PGCC cell cycles and contributions to cancer are still being defined. Filling this knowledge gap will lead to the development of improved cancer therapies. In this study, we used a molecular-genetic system in the model organism Drosophila melanogaster to examine how oncogenes interact with unscheduled endocycles in vivo. We found that several oncogenes promote bypass of an endocycle arrest, resulting in increased polyploid cell size and DNA content. The extent of this increased growth was dependent on the type of oncogenic mutation. When these polyploid cells returned to division, Ras^G12V promoted continued divisions of polyploid daughter cells with elevated genome instability. Ras^G12V expression during transient endocycles and subsequent divisions also induced expression of a matrix metalloprotease and a Wnt pathway ligand. Importantly, Ras^G12V with transient endocycles enhanced the growth of large, neoplastic tumors. These findings indicate that oncogenic mutations can synergize with transient, unscheduled endocycles to promote tumorigenesis with important broader implications for cancer prognosis and therapies.