학술논문
Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer
Document Type
Original Paper
Author
Cui Zhou, Daniel; Jayasinghe, Reyka G.; Chen, Siqi; Herndon, John M.; Iglesia, Michael D.; Navale, Pooja; Wendl, Michael C.; Caravan, Wagma; Sato, Kazuhito; Storrs, Erik; Mo, Chia-Kuei; Liu, Jingxian; Southard-Smith, Austin N.; Wu, Yige; Naser Al Deen, Nataly; Baer, John M.; Fulton, Robert S.; Wyczalkowski, Matthew A.; Liu, Ruiyang; Fronick, Catrina C.; Fulton, Lucinda A.; Shinkle, Andrew; Thammavong, Lisa; Zhu, Houxiang; Sun, Hua; Wang, Liang-Bo; Li, Yize; Zuo, Chong; McMichael, Joshua F.; Davies, Sherri R.; Appelbaum, Elizabeth L.; Robbins, Keenan J.; Chasnoff, Sara E.; Yang, Xiaolu; Reeb, Ashley N.; Oh, Clara; Serasanambati, Mamatha; Lal, Preet; Varghese, Rajees; Mashl, Jay R.; Ponce, Jennifer; Terekhanova, Nadezhda V.; Yao, Lijun; Wang, Fang; Chen, Lijun; Schnaubelt, Michael; Lu, Rita Jui-Hsien; Schwarz, Julie K.; Puram, Sidharth V.; Kim, Albert H.; Song, Sheng-Kwei; Shoghi, Kooresh I.; Lau, Ken S.; Ju, Tao; Chen, Ken; Chatterjee, Deyali; Hawkins, William G.; Zhang, Hui; Achilefu, Samuel; Chheda, Milan G.; Oh, Stephen T.; Gillanders, William E.; Chen, Feng; DeNardo, David G.; Fields, Ryan C.; Ding, Li
Source
Nature Genetics. 54(9):1390-1405
Subject
Language
English
ISSN
1061-4036
1546-1718
1546-1718
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.
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.
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.