Abstract SY29-01: Tracing the eco-evolutionary path of tumors to understand cancer

Abstract Tracing the eco-evolutionary path of tumors to understand cancer “Cancer is no more a disease of cells than a traffic jam is a disease of cars. A lifetime of study of the internal-combustion engine would not help anyone understand our traffic problems. ”David W. Smithers, 1962 Despite the advances in cancer prevention, early detection, and treatments, all of which have led to improved cancer survival, globally, there is an increased incidence in cancer-related deaths. Although each patient and each tumor is wholly unique, the tipping point to incurable disease is common across all patients: the dual capacity for cancers to metastasize and resist systemic treatment. The discovery of genetic mutations and epigenetic variation that emerges during cancer progression highlights that evolutionary and ecology principles can be used to understand how cancer evolves to a lethal phenotype. The evolution of metastasis, the spread of cancer to distal sites within the body, represents a lethal stage of cancer progression. Yet, the evolutionary dynamics that shape the emergence of metastatic disease remain unresolved. Using single-cell lineage tracing data in combination with phylogenetic statistical methods, we show that the evolutionary trajectory of metastatic disease is littered with bursts of rapid molecular change as new cellular subpopulations appear, a pattern known as punctuational evolution. Next, by measuring punctuational evolution across the metastatic cascade, we show that punctuational effects are concentrated within the formation of secondary tumours at distal metastatic sites, suggesting that qualitatively different modes of adaptation and evolution may drive primary and metastatic tumour progression. One example of eco-evolutionary adaptation is drug-tolerant persister cells (DTPs) that vade cell death during cytotoxic treatments by accessing transient adaptive states, allowing them to contribute to cancer progression after treatment. Cancer cells can survive genotoxic chemotherapy-induced stress by accessing a previously undescribed DTP state where mitotic bypass and continued endocycling promote survival by allowing cells to evade mitotic catastrophe and cell death. Mechanistic studies indicate that mitotic bypass is dependent on CDK1 inhibition by WEE1 and Myt1, which prevents entry into mitosis and induces premature APC/C activation during G2 arrest. Disrupting WEE1 or Myt1 activity using clinical-stage small molecule inhibitors promotes CDK1 reactivation, forcing mitotic entry, catastrophe, and cell death. Our results identify mitotic bypass and endocycling as a targetable mediator of cancer cell persistence that can be exploited for the eradication of DTPs. Our studies suggest that applying evolutionary ecology principles to define and design strategic interventions may alter the evolutionary trajectory of lethal cancer. Citation Format: Kenneth J. Pienta. Tracing the eco-evolutionary path of tumors to understand cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr SY29-01.