Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state
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ABSTRACT:
PROVIDER: PRJNA946712 | ENA |
REPOSITORIES: ENA
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Project description:The goal of this study was to investigate the transcriptional and epigenetic changes after the onset of KrasG12D and P53 Loss in Alveolar type 2 (AT2) cells using organoid model. Single cell Multi-omic sequencing were performed on 7 days tumor organoids which were derived from induced AT2 cells.
2025-08-31 | GSE227719 | GEO
Project description:Cancers display cellular, genetic and epigenetic heterogeneity, complicating disease modeling. Multiple cell states defined by gene expression have been described in lung adenocarcinoma (LUAD). However, the functional contributions of cell state and the regulatory programs that control chromatin and gene expression in the early stages of tumor initiation are not well understood. Using single-cell RNA and ATAC sequencing in Kras/p53-driven tumor organoids, we identified two major cellular states: one more closely resembling alveolar type 2 (AT2) cells (SPC-high), and the other with Epithelial-Mesenchymal-Transition (EMT)-associated gene expression (Hmga2-high). Each state exhibited distinct transcription factor networks, with SPC-high cells associated with TFs regulating AT2 fate and Hmga2-high cells enriched in Wnt- and NFκB-related TFs. CD44 was identified as a marker for the Hmga2-high state, enabling functional comparison of the two populations. Organoid assays and orthotopic transplantation revealed that SPC-high, CD44-negative cells exhibited higher tumorigenic potential within the lung microenvironment. These findings highlight the utility of organoids in understanding chromatin regulation in early tumorigenesis and identifying novel early stage therapeutic targets in Kras-driven LUAD.
| S-SCDT-10_1038-S44318-025-00376-6 | biostudies-other
Project description:Cancers display cellular, genetic and epigenetic heterogeneity, complicating disease modeling. Multiple cell states defined by gene expression have been described in lung adenocarcinoma (LUAD). However, the functional contributions of cell state and the regulatory programs that control chromatin and gene expression in the early stages of tumor initiation are not well understood. Using single-cell RNA and ATAC sequencing in Kras/p53-driven tumor organoids, we identified two major cellular states: one more closely resembling alveolar type 2 (AT2) cells (SPC-high), and the other with epithelial-mesenchymal-transition (EMT)-associated gene expression (Hmga2-high). Each state exhibited distinct transcription factor networks, with SPC-high cells associated with TFs regulating AT2 fate and Hmga2-high cells enriched in Wnt- and NFκB-related TFs. CD44 was identified as a marker for the Hmga2-high state, enabling functional comparison of the two populations. Organoid assays and orthotopic transplantation revealed that SPC-high, CD44-negative cells exhibited higher tumorigenic potential within the lung microenvironment. These findings highlight the utility of organoids in understanding chromatin regulation in early tumorigenesis and identifying novel early-stage therapeutic targets in Kras-driven LUAD.
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Project description:Alveolar epithelial regeneration is critical for normal lung function and becomes dysregulated in disease. While alveolar type 2 (AT2) and club cells are known distal lung epithelial progenitors, determining if alveolar epithelial type 1 (AT1) cells also contribute to alveolar regeneration has been hampered by lack of highly specific mouse models labeling AT1 cells. To address this, the Gramd2CreERT2 transgenic strain was generated and crossed to ROSAmTmG mice. Extensive cellular characterization, including distal lung immunofluorescence and cytospin staining, confirmed that GRAMD2+ AT1 cells are highly enriched for green fluoresecent protein (GFP). Interestingly, Gramd2CreERT2 GFP+ cells were able to form colonies in organoid co-culture with Mlg fibroblasts. Temporal scRNAseq revealed that Gramd2+ AT1 cells transition through numerous intermediate lung epithelial cell states including basal, secretory and AT2 cell in organoids while acquiring proliferative capacity. Our results indicate that Gramd2+ AT1 cells are highly plastic suggesting they may contribute to alveolar regeneration.
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Project description:The airways and the alveoli of the human respiratory tract are lined by two distinct types of epithelium. We previously established long-term expanding human lung epithelial organoids from lung tissues and developed a ‘proximal’ differentiation protocol to generate mucociliary airway organoids, yet the derivation of alveolar organoids from adult lung has remained a challenge. Here we defined a ‘distal’ differentiation approach to generate alveolar organoids from the same source that allows the establishment of airway organoids. Alveolar organoids are enriched for AT1 and AT2 cells and functionally simulate the alveolar epithelium. AT2 cells in lung organoids act as the progenitor cells from which alveolar organoids emerge. Moreover, we demonstrate productive SARS-CoV-2 infection of alveolar organoids. We further optimize 2-dimensional (2D) airway organoids. When differentiated under a slightly acidic pH, these 2D airway organoids sustain enhanced viral replication and better recapitulate the high infectivity of SARS-CoV-2. Moreover, the optimized 2D airway organoids can model IgG transcytosis across the airway epithelium. Collectively, we establish a bipotential organoid culture system that can reproducibly expand the entire human respiratory epithelium in vitro for modeling respiratory diseases, including COVID-19.
2022-06-22 | GSE189514 | GEO
Project description:An integrated organoid omics map extends modeling potential of kidney disease
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Project description:Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While existing genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are time-consuming and technically demanding. In contrast, cell line transplant models are fast and flexible, but these models fail to capture the full spectrum of disease progression. Organoid technologies provide a means to create next-generation cancer models that integrate the most advantageous features of autochthonous and transplant-based systems. However, robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 cells (AT2), a prominent cell-of-origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expression, the presence of lamellar bodies, and an ability to differentiate into the AT1 lineage. We used this system to develop flexible and versatile immunocompetent organoid-based models of KRAS, BRAF, and ALK-mutant LUAD. Notably, organoid-based tumors display extensive burden and complete penetrance, and are histopathologically indistinguishable from their autochthonous counterparts. Altogether, this organoid platform is a powerful, versatile new model system to study LUAD.
2023-01-02 | GSE213971 | GEO