Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state.
| العنوان: | Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state. |
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| المؤلفون: | Li J; Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston MA 02115 USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Dang SM; Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston MA 02115 USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Schurmann P; Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston MA 02115 USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.; Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands., Dost AFM; Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston MA 02115 USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Moye AL; Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston MA 02115 USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Paschini M; Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston MA 02115 USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Bhetariya PJ; Harvard Chan Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115., Bronson R; Rodent Histopathology Core, Harvard Medical School, Boston, MA 02115, USA., Sui SJH; Harvard Chan Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115., Kim CF; Stem Cell Program, Division of Hematology/Oncology and Pulmonary & Respiratory Diseases, Children's Hospital Boston, Boston MA 02115 USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. |
| المصدر: | Research square [Res Sq] 2023 Mar 14. Date of Electronic Publication: 2023 Mar 14. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101768035 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: Res Sq Subsets: PubMed not MEDLINE |
| مستخلص: | Alveolar type 2 (AT2) cells, the epithelial progenitor cells of the distal lung, are known to be the prominent cell of origin for lung adenocarcinoma. The regulatory programs that control chromatin and gene expression in AT2 cells during the early stages of tumor initiation are not well understood. Here, we dissected the response of AT2 cells to Kras activation and p53 loss (KP) using combined single cell RNA and ATAC sequencing in an established tumor organoid system. Multi-omic analysis showed that KP tumor organoid cells exhibit two major cellular states: one more closely resembling AT2 cells (SPC-high) and another with loss of AT2 identity (hereafter, Hmga2-high). These cell states are characterized by unique transcription factor (TF) networks, with SPC-high states associated with TFs known to regulate AT2 cell fate during development and homeostasis, and distinct TFs associated with the Hmga2-high state. CD44 was identified as a marker of the Hmga2-high state, and was used to separate organoid cultures for functional comparison of these two cell states. Organoid assays and orthotopic transplantation studies indicated that SPC-high cells have higher tumorigenic capacity in the lung microenvironment compared to Hmga2-high cells. These findings highlight the utility of understanding chromatin regulation in the early oncogenic versions of epithelial cells, which may reveal more effective means to intervene the progression of Kras-driven lung cancer. Competing Interests: Additional Declarations: There is NO Competing Interest. Declaration of Interests We declare no competing interests. C.F.K. and A.L.M. are founders of Cellforma. |
| تواريخ الأحداث: | Date Created: 20230330 Latest Revision: 20231020 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC10055547 |
| DOI: | 10.21203/rs.3.rs-2663901/v1 |
| PMID: | 36993454 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.21203/rs.3.rs-2663901/v1 |
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