Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells.

Autor:	Dost AFM; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Moye AL; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Vedaie M; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA., Tran LM; Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA., Fung E; Department of Surgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA., Heinze D; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; Section of Gastroenterology and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA., Villacorta-Martin C; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA., Huang J; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA., Hekman R; Center for Network Systems Biology, Boston University, Boston, MA 02118, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA., Kwan JH; Center for Network Systems Biology, Boston University, Boston, MA 02118, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA., Blum BC; Center for Network Systems Biology, Boston University, Boston, MA 02118, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA., Louie SM; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Rowbotham SP; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Sainz de Aja J; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Piper ME; Harvard T.H. Chan School of Public Health, Department of Biostatistics, Boston, MA 02115, USA., Bhetariya PJ; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Harvard T.H. Chan School of Public Health, Department of Biostatistics, Boston, MA 02115, USA., Bronson RT; Rodent Histopathology Core, Harvard Medical School, Boston, MA 02115, USA., Emili A; Center for Network Systems Biology, Boston University, Boston, MA 02118, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA; Department of Biology, Boston University, Boston, MA 02215, USA., Mostoslavsky G; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; Section of Gastroenterology and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA., Fishbein GA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA., Wallace WD; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USA., Krysan K; Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA., Dubinett SM; Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA., Yanagawa J; Department of Surgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: jyanagawa@mednet.ucla.edu., Kotton DN; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: dkotton@bu.edu., Kim CF; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: carla.kim@childrens.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell stem cell [Cell Stem Cell] 2020 Oct 01; Vol. 27 (4), pp. 663-678.e8. Date of Electronic Publication: 2020 Sep 04.
DOI:	10.1016/j.stem.2020.07.022
Abstrakt:	Mutant KRAS is a common driver in epithelial cancers. Nevertheless, molecular changes occurring early after activation of oncogenic KRAS in epithelial cells remain poorly understood. We compared transcriptional changes at single-cell resolution after KRAS activation in four sample sets. In addition to patient samples and genetically engineered mouse models, we developed organoid systems from primary mouse and human induced pluripotent stem cell-derived lung epithelial cells to model early-stage lung adenocarcinoma. In all four settings, alveolar epithelial progenitor (AT2) cells expressing oncogenic KRAS had reduced expression of mature lineage identity genes. These findings demonstrate the utility of our in vitro organoid approaches for uncovering the early consequences of oncogenic KRAS expression. This resource provides an extensive collection of datasets and describes organoid tools to study the transcriptional and proteomic changes that distinguish normal epithelial progenitor cells from early-stage lung cancer, facilitating the search for targets for KRAS-driven tumors. Competing Interests: Declaration of Interests W.D.W. is a member of the Leica Biosystems Medical Imaging Advisory Board. S.M.D. is on the Scientific Advisory Boards of EarlyDiagnostics; Johnson & Johnson Lung Cancer Initiative; LungLife AI; and T-Cure Bioscience. He has received research funding from Johnson & Johnson Lung Cancer Initiative and Novartis. C.F.K. has a sponsored research agreement from Celgene/BMS, but this funding did not support the research described in this manuscript. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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