Alveolar type I cells can give rise to KRAS-induced lung adenocarcinoma.
Minxiao Yang, Hua Shen, Per Flodby, Michael D Koss, Rania Bassiouni, Yixin Liu, Tea Jashashvili, Aaron Neely, Ezuka Ogbolu, Jonathan Castillo, Theresa Ryan Stueve, Daniel J Mullen, Amy L Ryan, John Carpten, Alessandra Castaldi, W Dean Wallace, Beiyun Zhou, Zea Borok, Crystal N Marconett
Author Information
Minxiao Yang: Department of Translational Genomics, University of Southern California, Los Angeles, CA 90089, USA; Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA 90089, USA.
Hua Shen: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Per Flodby: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Michael D Koss: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Rania Bassiouni: Department of Translational Genomics, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
Yixin Liu: Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA 90089, USA; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Tea Jashashvili: Department of Integrative Anatomical Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Aaron Neely: Department of Translational Genomics, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA 90089, USA.
Ezuka Ogbolu: Department of Translational Genomics, University of Southern California, Los Angeles, CA 90089, USA.
Jonathan Castillo: Department of Translational Genomics, University of Southern California, Los Angeles, CA 90089, USA; Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA 90089, USA.
Theresa Ryan Stueve: Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
Daniel J Mullen: Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
Amy L Ryan: Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa, IA 52242, USA.
John Carpten: Department of Translational Genomics, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
Alessandra Castaldi: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
W Dean Wallace: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Beiyun Zhou: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA 90089, USA; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Zea Borok: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Crystal N Marconett: Department of Translational Genomics, University of Southern California, Los Angeles, CA 90089, USA; Department of Surgery, University of Southern California, Los Angeles, CA 90089, USA; Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: crystal.marconett@med.usc.edu.
Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2) AT1 cells via oncogenic KRAS. Activation of KRAS in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8 intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2 AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.
