Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. We construct a high-resolution molecular landscape of the multicellular subtypes and spatial communities that compose PDAC using single-nucleus RNA-seq and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment-naïve. We uncovered recurrent expression programs across malignant cells and fibroblasts, including a newly-identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities with distinct contributions from malignant, fibroblast, and immune subtypes: classical, squamoid-basaloid, and treatment-enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.
In this repository, we present the analysis conducted for the whole transcriptome single nucleus sequencing.
Our manuscript (in press at Nature Genetics) will be available soon. The preprint can be found here. Raw and processed data can be found at GEO under accession number GSE202051. Code for the DSP analysis can be found here.