Alveolar epithelial type 1 cells serve as a cell of origin for lung adenocarcinoma with distinct molecular and phenotypic presentation

Lung adenocarcinoma (LUAD) is the most common subtype of cancer arising in the distal lung. LUAD encompasses several pathologic subtypes, each with 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 lung adenocarcinoma transcriptomes from The Cancer Genome Atlas revealed distinct alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cell signatures within human LUAD with significantly different survival outcomes between tumors expressing AT2 and AT1 gene signatures, suggesting AT1 cells might contribute to a subset of LUAD cases. To address this, we tested the ability of AT1 cells to give rise to LUAD following induction of KrasG12D, a known oncogenic driver of human LUAD. Activation of KrasG12D in Gram-domain containing 2 (Gramd2)+ AT1 cells gave rise to multiple LUAD lesions, primarily of papillary histology. In contrast, activation of KrasG12D in surfactant protein C (Sftpc+) AT2 cells resulted in LUAD lesions of 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. 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 the 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.