NYU Single-Cell Map of 480,000 PDAC Cells Shows MYC-Driven State Switching Fuels Clonal Escape

Researchers at NYU Langone performed single-cell DNA and RNA sequencing on 31 treatment-naïve and post-chemotherapy PDAC tumors, generating clonal phylogenies that tracked genetic and transcriptional plasticity over disease progression. This approach exposed how distinct clones within the same tumor independently acquire MYC amplification or enhancer hijacking, enabling reversible transitions from classical to basal states previously viewed as fixed subtypes. The granular resolution overturned bulk-tumor studies that averaged signals and missed intra-tumoral switching. Laboratory inhibition of MYC in basal-dominant organoids restored classical markers, increased MHC-I expression, and heightened T-cell recognition, directly linking the gene to both aggressiveness and immune evasion. These results position clonal plasticity as a core driver of the 85 percent five-year mortality rate rather than a secondary feature.