Transcriptomic Plasticity is a Hallmark of Metastatic Pancreatic Cancer

Abstract Metastasis is the leading cause of cancer deaths. To develop strategies for intercepting metastatic progression, a better understanding of how tumor cells adapt to vastly different organ contexts is needed. To investigate this question, a single-cell transcriptomic atlas of primary tumor and diverse metastatic samples (liver, omentum, peritoneum, stomach wall, lymph node, and diaphragm) from a patient with pancreatic ductal adenocarcinoma who underwent rapid autopsy was generated. Using unsupervised archetype analysis, both shared and site-specific gene programs were identified, including lipid metabolism and gastrointestinal programs prevalent in peritoneal and stomach wall lesions, respectively. We developed PICASSO as a probabilistic approach for inferring clonal phylogeny from single-cell and matched whole-exome sequencing data. Comparison of PICASSO-generated clonal structure with phenotypic signatures revealed that pancreatic cancer cells adapted to local environments with minimal contribution from clonal genotype. Our results suggest a paradigm whereby strong environmental effects are imposed on highly plastic cancer cells during metastatic dissemination.