Faculty, Staff and Student Publications
Publication Date
9-1-2022
Journal
Nature Genetics
Abstract
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.
Keywords
Carcinoma, Pancreatic Ductal, Cell Transformation, Neoplastic, Humans, Pancreas, Pancreatic Neoplasms, Tumor Microenvironment
DOI
10.1038/s41588-022-01157-1
PMID
35995947
PMCID
PMC9470535
PubMedCentral® Posted Date
8-22-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Gastroenterology Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons