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

doi:10.1016/j.celrep.2023.113286

Alveolar type I cells can give rise to KRAS-induced lung adenocarcinoma

Cell Rep. 2023 Dec 26;42(12):113286. doi: 10.1016/j.celrep.2023.113286. Epub 2023 Nov 22.

Authors

Minxiao Yang¹, Hua Shen², Per Flodby², Michael D Koss³, Rania Bassiouni⁴, Yixin Liu⁵, Tea Jashashvili⁶, Aaron Neely⁷, Ezuka Ogbolu⁸, Jonathan Castillo¹, Theresa Ryan Stueve⁹, Daniel J Mullen⁹, Amy L Ryan¹⁰, John Carpten⁴, Alessandra Castaldi¹¹, W Dean Wallace³, Beiyun Zhou¹², Zea Borok¹¹, Crystal N Marconett¹³

Affiliations

¹ 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.
² Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
³ 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.
⁴ 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.
⁵ 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.
⁶ Department of Integrative Anatomical Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ 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.
⁸ Department of Translational Genomics, University of Southern California, Los Angeles, CA 90089, USA.
⁹ 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.
¹⁰ Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa, IA 52242, USA.
¹¹ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹² 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.
¹³ 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.

Abstract

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^G12D. Activation of KRAS^G12D 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.

Keywords: CP: Cancer; KRT8(+) intermediate cell states; Kras(G12D) signaling; alveolar epithelial cells; cell of origin; lung cancer; oncogenesis; spatial transcriptomic sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung* / genetics
Adenocarcinoma of Lung* / pathology
Animals
Cell Transformation, Neoplastic / metabolism
Lung Neoplasms* / pathology
Mice
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism

Substances

Proto-Oncogene Proteins p21(ras)
Hras protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding