Early-stage lung cancer is driven by a transitional cell state dependent on a KRAS-ITGA3-SRC axis.

Autor:	Moye AL; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.; Harvard Stem Cell Institute, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA., Dost AF; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.; Harvard Stem Cell Institute, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA.; Hubrecht Institute, Oncode Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, The Netherlands., Ietswaart R; Department of Genetics, Harvard Medical School, Boston, MA, USA., Sengupta S; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.; Harvard Stem Cell Institute, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA., Ya V; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.; Harvard Stem Cell Institute, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA., Aluya C; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.; Harvard Stem Cell Institute, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA., Fahey CG; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.; Harvard Stem Cell Institute, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA.; Harvard University and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Louie SM; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.; Harvard Stem Cell Institute, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA., Paschini M; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.; Harvard Stem Cell Institute, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA., Kim CF; Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA. carla.kim@childrens.harvard.edu.; Harvard Stem Cell Institute, Cambridge, MA, USA. carla.kim@childrens.harvard.edu.; Department of Genetics, Harvard Medical School, Boston, MA, USA. carla.kim@childrens.harvard.edu.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Jul; Vol. 43 (14), pp. 2843-2861. Date of Electronic Publication: 2024 May 16.
DOI:	10.1038/s44318-024-00113-5
Abstrakt:	Glycine-12 mutations in the GTPase KRAS (KRAS G12 ) are an initiating event for development of lung adenocarcinoma (LUAD). KRAS G12 mutations promote cell-intrinsic rewiring of alveolar type-II progenitor (AT2) cells, but to what extent such changes interplay with lung homeostasis and cell fate pathways is unclear. Here, we generated single-cell RNA-seq (scRNA-seq) profiles from AT2-mesenchyme organoid co-cultures, mice, and stage-IA LUAD patients, identifying conserved regulators of AT2 transcriptional dynamics and defining the impact of KRAS G12D mutation with temporal resolution. In AT2 WT organoids, we found a transient injury/plasticity state preceding AT2 self-renewal and AT1 differentiation. Early-stage AT2 KRAS cells exhibited perturbed gene expression dynamics, most notably retention of the injury/plasticity state. The injury state in AT2 KRAS cells of patients, mice, and organoids was distinguishable from AT2 WT states via altered receptor expression, including co-expression of ITGA3 and SRC. The combination of clinically relevant KRAS G12D and SRC inhibitors impaired AT2 KRAS organoid growth. Together, our data show that an injury/plasticity state essential for lung repair is co-opted during AT2 self-renewal and LUAD initiation, suggesting that early-stage LUAD may be susceptible to interventions that target specifically the oncogenic nature of this cell state. (© 2024. The Author(s).)
Databáze:	MEDLINE
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