Spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment
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Dataset information
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here we construct a high-resolution molecular landscape of the multicellular subtypes and spatial communities that compose PAC using single-nucleus RNA-seq and whole-transcriptome digital spatial profiling (SP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment-naïve. We uncovered expression programs across malignant cells and fibroblasts, including a newly-identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities: classical, squamoid-basaloid, and treatment-enriched. Our refined molecular and cellular taxonomy can advance precision oncology in PAC through stratification in clinical trials and as roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here we construct a high-resolution molecular landscape of the multicellular subtypes and spatial communities that compose PAC using single-nucleus RNA-seq and whole-transcriptome digital spatial profiling (SP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment-naïve. We uncovered expression programs across malignant cells and fibroblasts, including a newly-identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities: classical, squamoid-basaloid, and treatment-enriched. Our refined molecular and cellular taxonomy can advance precision oncology in PAC through stratification in clinical trials and as roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.
Overall design
14 specimens received no treatment prior to resection; 7 specimens received neoadjuvant chemotherapy, radiotherapy, losartan, and/or nivolumab prior to resection
14 specimens received no treatment prior to resection; 7 specimens received neoadjuvant chemotherapy, radiotherapy, losartan, and/or nivolumab prior to resection
Technology
GeoMx DSP
GeoMx DSP
Platform
Illumina NovaSeq 6000 (Homo sapiens)
Illumina NovaSeq 6000 (Homo sapiens)
Species
Homo sapiens
Tissues
Pancreas
Pancreas
Disease
Pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma
Submission date: 2022-03-21Update date: 2022-05-13
Contributors
Hwang, William L; Jagadeesh, Karthik A; Guo, Jimmy A; Hoffman, Hannah I; Su, Jennifer; Shiau, Carina; Jacks, Tyler; Regev, Aviv
Accessions
GEO Series Accessions:
GSE199102