@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 = "Funding Information: We thank the patients, staff and scientists who contributed to this study as well as the NCI and the Human Tumor Atlas Network (HTAN) consortium. All HTAN consortium members are named at humantumoratlas.org. We also thank the Siteman Cancer Center and the McDonnell Genome Institute for their support. The following grants supported this work: grant no. U2CCA233303 to L.D., R.C.F., W.E.G. and S.T.O.; grant no. U24CA211006 to L.D.; grant no. U24CA209837 to K.I.S.; grant no. R01HG009711 to L.D. and F.C. Funding Information: We thank the patients, staff and scientists who contributed to this study as well as the NCI and the Human Tumor Atlas Network (HTAN) consortium. All HTAN consortium members are named at humantumoratlas.org. We also thank the Siteman Cancer Center and the McDonnell Genome Institute for their support. The following grants supported this work: grant no. U2CCA233303 to L.D., R.C.F., W.E.G. and S.T.O.; grant no. U24CA211006 to L.D.; grant no. U24CA209837 to K.I.S.; grant no. R01HG009711 to L.D. and F.C. 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",
}