Abstract 5: Alveolar epithelial type 1 cells can serve as a cell of origin for lung adenocarcinoma with distinct molecular and phenotypic presentation
Authors: Yang Minxiao , Shen Hua , Flodby Per , Koss Michael , Bassiouni Rania , Liu Yixin , Stueve Theresa Ryan , Mullen Daniel J. , Ryan Amy L. , Jashashvili Tea , Carpten John , Castaldi Alessandra , Wallace W. Dean , Zhou Beiyun , Borok Zea , Marconett Crystal N. 
Published: April 2023

Abstract
Lung adenocarcinoma (LUAD) is the most common subtype of cancer arising in the distal lung. LUAD encompasses several pathologic histologies, some with important differing clinical outcomes and biological behaviors. However, the molecular and cellular underpinnings of the different subtypes are largely unknown. Understanding which cell populations in the distal lung contribute to LUAD could provide insights into the marked heterogeneity in pathologic features, clinical presentation and responses to therapy of LUAD. Differential expression analysis of LUAD transcriptomes from The Cancer Genome Atlas revealed distinct alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cell signatures with significantly different survival outcomes between tumors expressing AT2 and AT1 gene signatures. The data suggests that AT1 cells might contribute to a subset of LUAD cases. To determine if AT1 cells could give rise to LUAD, we utilized transgenic mouse models to induce KrasG12D, a known oncogenic driver of human LUAD, in Gram-domain containing 2 (Gramd2)+ expressing AT1 cells. This gave rise to multiple LUAD lesions, as confirmed by micro computed tomography and pathologist-evaluated hematoxylin and eosin staining, primarily of papillary histology. In contrast, activation of KrasG12D in surfactant protein C (Sftpc+) AT2 cells resulted in LUAD lesions of exclusively lepidic histology. Immunohistochemistry established that Gramd2:KrasG12D lesions were of primary lung origin and not metastatic events. Spatial transcriptomic profiling revealed distinct pathway alterations within Gramd2- and Sftpc-derived LUAD, including specific upregulation of TGFβ-mediated epithelial to mesenchymal transition (EMT) in Gramd2+ AT1 LUAD. Immunofluorescence confirmed differences observed in the spatial transcriptomic analysis in expression patterns and distribution of cell-specific markers depending on cell of origin, while universal upregulation of a Krt8+ intermediate cell state marker was observed. Our results are consistent with Gramd2+ AT1 cells serving as a putative cell of origin for LUAD and suggest that LUAD may be a collection of adenocarcinomas that share a common location within the distal lung but arise from different cells of origin, a finding with potentially important therapeutic implications.
Citation Format: Minxiao Yang, Hua Shen, Per Flodby, Michael Koss, Rania Bassiouni, Yixin Liu, Theresa Ryan Stueve, Daniel J. Mullen, Amy L. Ryan, Tea Jashashvili, John Carpten, Alessandra Castaldi, W. Dean Wallace, Beiyun Zhou, Zea Borok, Crystal N. Marconett. Alveolar epithelial type 1 cells can serve as a cell of origin for lung adenocarcinoma with distinct molecular and phenotypic presentation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5.