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
Affiliations
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; Corresponding author
Summary: 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 KRASG12D. Activation of KRASG12D 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.
