@article{aa9a5e3b6ad4456896154c8a6575f59e,
title = "Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer",
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-na{\"i}ve 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.",
author = "\{Cui Zhou\}, Daniel and Jayasinghe, \{Reyka G.\} and Siqi Chen and Herndon, \{John M.\} and Iglesia, \{Michael D.\} and Pooja Navale and Wendl, \{Michael C.\} and Wagma Caravan and Kazuhito Sato and Erik Storrs and Mo, \{Chia Kuei\} and Jingxian Liu and Southard-Smith, \{Austin N.\} and Yige Wu and \{Naser Al Deen\}, Nataly and Baer, \{John M.\} and Fulton, \{Robert S.\} and Wyczalkowski, \{Matthew A.\} and Ruiyang Liu and Fronick, \{Catrina C.\} and Fulton, \{Lucinda A.\} and Andrew Shinkle and Lisa Thammavong and Houxiang Zhu and Hua Sun and Wang, \{Liang Bo\} and Yize Li and Chong Zuo and McMichael, \{Joshua F.\} and Davies, \{Sherri R.\} and Appelbaum, \{Elizabeth L.\} and Robbins, \{Keenan J.\} and Chasnoff, \{Sara E.\} and Xiaolu Yang and Reeb, \{Ashley N.\} and Clara Oh and Mamatha Serasanambati and Preet Lal and Rajees Varghese and Mashl, \{Jay R.\} and Jennifer Ponce and Terekhanova, \{Nadezhda V.\} and Lijun Yao and Fang Wang and Lijun Chen and Michael Schnaubelt and Lu, \{Rita Jui Hsien\} and Schwarz, \{Julie K.\} and Puram, \{Sidharth V.\} and Kim, \{Albert H.\} and Song, \{Sheng Kwei\} and Shoghi, \{Kooresh I.\} and Lau, \{Ken S.\} and Tao Ju and Ken Chen and Deyali Chatterjee and Hawkins, \{William G.\} and Hui Zhang and Samuel Achilefu and Chheda, \{Milan G.\} and Oh, \{Stephen T.\} and Gillanders, \{William E.\} and Feng Chen and DeNardo, \{David G.\} and Fields, \{Ryan C.\} and Li Ding",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = sep,
doi = "10.1038/s41588-022-01157-1",
language = "English",
volume = "54",
pages = "1390--1405",
journal = "Nature Genetics",
issn = "1061-4036",
number = "9",
}