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

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