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Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer


Cui Zhou DDaniel , Jayasinghe RGReyka G , Chen SSiqi , Herndon JMJohn M , Iglesia MDMichael D , Navale PPooja , Wendl MCMichael C , Caravan WWagma , Sato KKazuhito , Storrs EErik , Mo CKChia-Kuei , Liu JJingxian , Southard-Smith ANAustin N , Wu YYige , Naser Al Deen NNataly , Baer JMJohn M , Fulton RSRobert S , Wyczalkowski MAMatthew A , Liu RRuiyang , Fronick CCCatrina C , Fulton LALucinda A , Shinkle AAndrew , Thammavong LLisa , Zhu HHouxiang , Sun HHua , Wang LBLiang-Bo , Li YYize , Zuo CChong , McMichael JFJoshua F , Davies SRSherri R , Appelbaum ELElizabeth L , Robbins KJKeenan J , Chasnoff SESara E , Yang XXiaolu , Reeb ANAshley N , Oh CClara , Serasanambati MMamatha , Lal PPreet , Varghese RRajees , Mashl JRJay R , Ponce JJennifer , Terekhanova NVNadezhda V , Yao LLijun , Wang FFang , Chen LLijun , Schnaubelt MMichael , Lu RJRita Jui-Hsien , Schwarz JKJulie K , Puram SVSidharth V , Kim AHAlbert H , Song SKSheng-Kwei , Shoghi KIKooresh I , Lau KSKen S , Ju TTao , Chen KKen , Chatterjee DDeyali , Hawkins WGWilliam G , Zhang HHui , Achilefu SSamuel , Chheda MGMilan G , Oh STStephen T , Gillanders WEWilliam E , Chen FFeng , DeNardo DGDavid G , Fields RCRyan C , Ding LLi . Nature genetics. 2022 08 22; ().


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.