This study investigates the genomic instability and clonal dynamics in metastatic pancreatic cancer. The researchers sequenced 13 patients with pancreatic adenocarcinoma to identify somatically acquired genomic rearrangements. They found that pancreatic cancer is characterized by telomere dysfunction and abnormal cell-cycle control, leading to dysregulated G1-to-S phase transition with an intact G2-M checkpoint. These rearrangements often persist after cancer dissemination, resulting in ongoing parallel evolution among different metastases. The study also revealed genetic heterogeneity among metastasis-initiating cells and evidence of clonal evolution within metastases. Phylogenetic analysis showed organ-specific branches, suggesting that metastasis may require driver mutations beyond those required for the primary tumor. The findings highlight the complexity and adaptability of cancer under different selection pressures, which could inform the development of targeted therapies.This study investigates the genomic instability and clonal dynamics in metastatic pancreatic cancer. The researchers sequenced 13 patients with pancreatic adenocarcinoma to identify somatically acquired genomic rearrangements. They found that pancreatic cancer is characterized by telomere dysfunction and abnormal cell-cycle control, leading to dysregulated G1-to-S phase transition with an intact G2-M checkpoint. These rearrangements often persist after cancer dissemination, resulting in ongoing parallel evolution among different metastases. The study also revealed genetic heterogeneity among metastasis-initiating cells and evidence of clonal evolution within metastases. Phylogenetic analysis showed organ-specific branches, suggesting that metastasis may require driver mutations beyond those required for the primary tumor. The findings highlight the complexity and adaptability of cancer under different selection pressures, which could inform the development of targeted therapies.