期刊
NATURE GENETICS
卷 54, 期 8, 页码 1178-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-022-01134-8
关键词
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资金
- Ludwig Institute for Cancer Research
- Klarman Cell Observatory
- Lustgarten Foundation
- American Society for Clinical Oncology/Conquer Cancer Foundation Young Investigator Award
- Hopper-Belmont Foundation Inspiration Award
- American Cancer Society/Massachusetts General Hospital Institutional Research Grant
- UCSF Dean's Yearlong Fellowship
- Swiss National Science Foundation [P2ZHP3 181475]
- SU2C-Lustgarten Foundation
- Robert L. Fine Cancer Research Foundation
- Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through Government of Ontario
- Wallace McCain Centre for Pancreatic Cancer - Princess Margaret Cancer Foundation
- Terry Fox Research Institute
- Canadian Cancer Society Research Institute
- Pancreatic Cancer Canada Foundation
- NCI Cancer Moonshot grant [U01-CA224348]
- Ludwig Cancer Center at Harvard
- Swiss National Science Foundation (SNF) [P2ZHP3_181475] Funding Source: Swiss National Science Foundation (SNF)
This study provides a high-resolution molecular landscape of pancreatic ductal adenocarcinoma (PDAC) using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling. It identifies recurrent expression programs in malignant cells and fibroblasts, including a newly identified neural-like progenitor malignant cell program associated with poor prognosis. The study also reveals three multicellular communities with distinct contributions from malignant, fibroblast and immune subtypes. This refined molecular and cellular classification can guide clinical trials and therapeutic targeting for 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 cellular subtypes and spatial communities that compose PDAC using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment naive. We uncovered recurrent 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 with distinct contributions from malignant, fibroblast and immune subtypes: classical, squamoid-basaloid and treatment enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions. Single-nucleus and spatial, whole-transcriptome profiling of 43 pancreatic adenocarcinomas provides a refined molecular and cellular classification, highlighting a new neoadjuvant treatment-associated neural-like progenitor tumor cell state.
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