# Elucidating the Cellular Origins of lung adenocarcinoma > **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2023 · $409,017 ## Abstract Lung cancer is responsible for the most cancer-related deaths in the United States, and Lung adenocarcinoma (LUAD) is the major histologic subtype. LUAD presents clinically with four major histologic subtypes (lepidic, acinar, papillary and solid), has variable presentation of EGFR and Kras mutations depending on ethnicity, age, and sex, and can be subclassified into four separate categories based on genome-wide DNA methylation profiles. To date, there is little connection between these widely disparate manifestations of LUAD besides their effects on overall patient survival. There is evidence in mouse models to suggest that the majority of LUAD arise from surfactant protein c (Sftpc)-positive alveolar epithelial type 2 (AT2) cells, and that Scgb1a1-positive club cells can also contribute a fraction of LUAD cases. However, it is unknown if LUAD can arise from AT1 cells, the other major epithelial cell type in the distal lung that covers 95% of the alveolar surface. AT1 cells were historically thought to be terminally differentiated. However, we have recently developed a Gramd2-driven CreERT2 mouse model that specifically activated the KrasG12D oncogenic driver in AT1 cells, and found that AT1 cells can serve as a cell of origin for LUAD with predominantly papillary histology and distinct transcriptomic signatures, including increased transforming growth factor beta (TGF-β)-mediated epithelial to mesenchymal transition (EMT). This is in contrast to AT2 cell-specific Sftpc-driven KrasG12D, which resulted exclusively in lepidic LUAD and was enriched for VEGF-mediated angiogenesis. Therefore, we hypothesize that LUAD, as it is currently defined, may actually be a collection of at least 4 adenocarcinoma subtypes that arise in the distal alveolar compartment from different cells of origin, and that the great variation we see in LUAD presentation and clinical outcome can be explained in part by which cell type LUAD arises in. However; several questions remain. We do not know if the oncogenic driver in AT1 cells influences histologic presentation. We will therefore (Aim 1) characterize Gramd2-CreERT2 driven EGFR mutations, the other major oncogenic driver in LUAD. It is also possible that induction of KrasG12D in AT1 cells results in disrupted tumor microenvironments that stimulate AT2 cells; we will therefore (2) perform GFP+ lineage tracing to determine in vitro and in vivo cell contributions to tumor formation. We will also establish the translational implications of our prior research (Aim 3) and utilize inhibitors of TGFβ that have succeeded in preclinical models but failed in clinical trials to determine if cell of origin influences response to therapy in both mouse models and unique human patient LUAD cohorts. Understanding the connection between cell of origin and clinical presentation will allow for enhanced patient stratification, improved assessment of best therapeutic outcomes, and potential reclassification of LUAD into multiple cancer types... ## Key facts - **NIH application ID:** 11075714 - **Project number:** 7R01CA262258-02 - **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE - **Principal Investigator:** Crystal Nicole Marconett - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2023 - **Award amount:** $409,017 - **Award type:** 7 - **Project period:** 2023-07-11 → 2029-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/11075714 ## Citation > US National Institutes of Health, RePORTER application 11075714, Elucidating the Cellular Origins of lung adenocarcinoma (7R01CA262258-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11075714. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*