To EMT or not to EMT: Ablation of mesenchymal tumor cell lineages reveals the essential role of EMT in pancreatic cancer initiation and evolution

Abstract Epithelial-to-mesenchymal transition (EMT), a complex biological pathway that facilitates cellular plasticity, is used by tumor cells to enable metastasis and drug resistance. Our functional understanding of the impact of EMT on cancer has been limited by the lack of effective tools to ablate tumor cells as they become mesenchymal. In a recent study published in Nature, Perelli and colleagues used elegant genetically engineered lineage tracing and ablation strategies to track and eliminate tumor cells as they undergo EMT in pancreatic cancer. In a two-pronged approach, they queried the functional consequences of ablating EMT tumor cells before pancreatic ductal adenocarcinoma (PDAC) formation or in advanced PDAC tumors. These experiments collectively revealed that epithelial tumor cells only progress to low-grade lesions with minimal proliferative potential, while mesenchymal tumor cells undergo EMT early on to become malignant and metastasize. Profiling of mesenchymal tumor cell lineages revealed an altered chromatin landscape that leads to chromosomal instability (CIN) and disease progression. CIN is facilitated through complex structural rearrangements and chromothripsis, ultimately driving increased tumor heterogeneity and enhanced proliferation in EMT cells. This work reveals that EMT is an important driver of tumor heterogeneity and progression as a downstream consequence of CIN and provides mechanistic insight into how cellular plasticity can lead to genomic changes that drive disease progression.