@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",
}