Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer.
Daniel Cui ZhouReyka G JayasingheSiqi ChenJohn M HerndonMichael D IglesiaPooja NavaleMichael C WendlWagma CaravanKazuhito SatoErik StorrsChia-Kuei MoJingxian LiuAustin N Southard-SmithYige WuNataly Naser Al DeenJohn M BaerRobert S FultonMatthew A WyczalkowskiRuiyang LiuCatrina C FronickLucinda A FultonAndrew ShinkleLisa ThammavongHouxiang ZhuHua SunLiang-Bo WangYize LiChong ZuoJoshua F McMichaelSherri R DaviesElizabeth L AppelbaumKeenan J RobbinsSara E ChasnoffXiaolu YangAshley N ReebClara OhMamatha SerasanambatiPreet LalRajees VargheseJay R MashlJennifer PonceNadezhda V TerekhanovaLijun YaoFang WangLijun ChenMichael SchnaubeltRita Jui-Hsien LuJulie K SchwarzSidharth V PuramAlbert H KimSheng-Kwei SongKooresh I ShoghiKen S LauTao JuKen ChenDeyali ChatterjeeWilliam G HawkinsHui ZhangSamuel AchilefuMilan G ChhedaStephen T OhWilliam E GillandersFeng ChenDavid G DeNardoRyan C FieldsLi DingPublished in: Nature genetics (2022)
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.
Keyphrases
- single cell
- rna seq
- regulatory t cells
- copy number
- high throughput
- mitochondrial dna
- high grade
- high resolution
- genome wide
- photodynamic therapy
- newly diagnosed
- end stage renal disease
- ejection fraction
- induced apoptosis
- combination therapy
- poor prognosis
- prognostic factors
- stem cells
- peritoneal dialysis
- oxidative stress
- cancer therapy
- locally advanced
- immune response
- cell cycle arrest
- cell therapy
- long non coding rna
- drug delivery
- big data
- extracellular matrix
- mass spectrometry
- fluorescence imaging
- stress induced