Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer

Nat Genet. 2022 Sep;54(9):1390-1405. doi: 10.1038/s41588-022-01157-1. Epub 2022 Aug 22.


Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinoma, Pancreatic Ductal* / metabolism
  • Cell Transformation, Neoplastic / genetics
  • Humans
  • Pancreas / metabolism
  • Pancreatic Neoplasms* / metabolism
  • Tumor Microenvironment / genetics

Supplementary concepts

  • Pancreatic Carcinoma