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Clonal Heterogeneity in Human Pancreatic Ductal Adenocarcinoma and Its Impact on Tumor Progression

This study of primary human pancreatic ductal adenocarcinoma (PDAC) tumors (n=62) aims to characterize intratumoral clonal diversity, transcriptional plasticity, tumor–microenvironment interactions, and spatial patterns associated with progression and metastasis. Combined single-cell RNA sequencing and spatial transcriptomics enabled reconstruction of tumor phylogenies and mapping of clone-specific transcriptional states. Extensive intratumoral heterogeneity was observed, with multiple genetically distinct neoplastic clones coexisting within tumors. Distinct clones exhibited unique interactions with stromal and immune cells, and dispersed clones enriched for epithelial-to-mesenchymal transition (EMT) programs and immune-suppressive microenvironments correlated with metastatic potential and lymph node colonization. A recurrent classical-to-basal clonal transition associated with MYC amplification and reduced immune response was identified and experimentally validated, implicating clonal evolution in emergence of more aggressive phenotypes. Controlled-access dbGaP deposits will include raw sequencing data from single-cell RNA sequencing and spatial transcriptomics experiments and de-identified clinical/sample metadata.