Journal
NATURE GENETICS
Volume 54, Issue 9, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-022-01157-1
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Funding
- Siteman Cancer Center
- McDonnell Genome Institute
- [U2CCA233303]
- [U24CA211006]
- [U24CA209837]
- [R01HG009711]
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This multi-omic analysis of pancreatic cancer identified spatially resolved, heterogeneous cell populations and revealed treatment-related changes in communication between tumor and stromal cells. The study provides a deeper understanding of the substructure of pancreatic ductal adenocarcinoma and may contribute to improved therapy for patients with this disease.
A multi-omic analysis of pancreatic cancer identifies spatially resolved, heterogeneous cell populations including transitional cell types. Analysis of primary samples identifies treatment-related changes in cross-talk between tumor and stromal cells. Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naive 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.
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