Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment.

Autor:	Hwang WL; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Jagadeesh KA; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Guo JA; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; School of Medicine, University of California, San Francisco, San Francisco, CA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA., Hoffman HI; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.; Harvard-MIT MD/PhD and Health Sciences and Technology Program, Harvard Medical School, Boston, MA, USA., Yadollahpour P; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Reeves JW; NanoString Technologies, Seattle, WA, USA., Mohan R; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Drokhlyansky E; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Van Wittenberghe N; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ashenberg O; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Farhi SL; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Schapiro D; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.; Institute for Computational Biomedicine and Institute of Pathology, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany., Divakar P; NanoString Technologies, Seattle, WA, USA., Miller E; NanoString Technologies, Seattle, WA, USA., Zollinger DR; NanoString Technologies, Seattle, WA, USA., Eng G; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Schenkel JM; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Su J; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Shiau C; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Yu P; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Freed-Pastor WA; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Abbondanza D; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Mehta A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Gould J; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Lambden C; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Porter CBM; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Tsankov A; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Dionne D; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Waldman J; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Cuoco MS; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Nguyen L; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Delorey T; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Phillips D; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Genentech, South San Francisco, CA, USA., Barth JL; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Kem M; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Rodrigues C; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Ciprani D; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Roldan J; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Zelga P; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Jorgji V; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Chen JH; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Ely Z; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Zhao D; New York Medical College, Valhalla, NY, USA., Fuhrman K; NanoString Technologies, Seattle, WA, USA., Fropf R; NanoString Technologies, Seattle, WA, USA., Beechem JM; NanoString Technologies, Seattle, WA, USA., Loeffler JS; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Ryan DP; Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Weekes CD; Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Ferrone CR; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Qadan M; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Aryee MJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Jain RK; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Edwin L. Steele Laboratory for Tumor Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Neuberg DS; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA., Wo JY; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Hong TS; Center for Systems Biology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Xavier R; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Aguirre AJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Rozenblatt-Rosen O; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Genentech, South San Francisco, CA, USA., Mino-Kenudson M; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Castillo CF; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Liss AS; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Ting DT; Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Jacks T; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. aviv.regev.sc@gmail.com., Regev A; Broad Institute of MIT and Harvard, Cambridge, MA, USA. tjacks@mit.edu.; Genentech, South San Francisco, CA, USA. tjacks@mit.edu.
Jazyk:	angličtina
Zdroj:	Nature genetics [Nat Genet] 2022 Aug; Vol. 54 (8), pp. 1178-1191. Date of Electronic Publication: 2022 Jul 28.
DOI:	10.1038/s41588-022-01134-8
Abstrakt:	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. (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze:	MEDLINE
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