Early-stage lung cancer is driven by a transitional cell state dependent on a KRAS-ITGA3-SRC axis.
| Title: | Early-stage lung cancer is driven by a transitional cell state dependent on a KRAS-ITGA3-SRC axis. |
|---|---|
| Authors: | Moye, Aaron L1,2,3 (AUTHOR), Dost, Antonella FM1,2,3,4 (AUTHOR), Ietswaart, Robert3 (AUTHOR), Sengupta, Shreoshi1,2,3 (AUTHOR), Ya, VanNashlee1,2,3 (AUTHOR), Aluya, Chrystal1,2,3 (AUTHOR), Fahey, Caroline G1,2,3,5 (AUTHOR), Louie, Sharon M1,2,3 (AUTHOR), Paschini, Margherita1,2,3 (AUTHOR), Kim, Carla F1,2,3 (AUTHOR) carla.kim@childrens.harvard.edu |
| Source: | EMBO Journal. Jul2024, Vol. 43 Issue 14, p2843-2861. 19p. |
| Subject Terms: | *LUNG cancer, *GENE expression, *PROGENITOR cells, *RAS oncogenes, *GUANOSINE triphosphatase |
| Abstract: | Glycine-12 mutations in the GTPase KRAS (KRASG12) are an initiating event for development of lung adenocarcinoma (LUAD). KRASG12 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 KRASG12D mutation with temporal resolution. In AT2WT organoids, we found a transient injury/plasticity state preceding AT2 self-renewal and AT1 differentiation. Early-stage AT2KRAS cells exhibited perturbed gene expression dynamics, most notably retention of the injury/plasticity state. The injury state in AT2KRAS cells of patients, mice, and organoids was distinguishable from AT2WT states via altered receptor expression, including co-expression of ITGA3 and SRC. The combination of clinically relevant KRASG12D and SRC inhibitors impaired AT2KRAS 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. Synopsis: KRASG12 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. This study investigates the epigenetic and transcriptomic responses of AT2 cells to specific oncogenic events. AT2WT organoids adopt a transient, transitional injury/plasticity state prior to both AT2 self-renewal and AT1 differentiation. AT2KRAS cells co-opt and retain the transitional injury/plasticity state. AT2KRAS cells in patients, mice, and organoids differ from AT2WT cells by altered gene expression, including co-expression of ITGA3 and SRC. AT2KRAS cells in patients, mice, and organoids can be targeted using clinically-relevant KRASG12D and SRC inhibitors. KRASG12 mutations cause persistence of a normally transient injury/plasticity state in progenitor cells, leading to initiation of lung adenocarcinoma. [ABSTRACT FROM AUTHOR] |
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| Items | – Name: Title Label: Title Group: Ti Data: Early-stage lung cancer is driven by a transitional cell state dependent on a KRAS-ITGA3-SRC axis. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Moye%2C+Aaron+L%22">Moye, Aaron L</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Dost%2C+Antonella+FM%22">Dost, Antonella FM</searchLink><relatesTo>1,2,3,4</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ietswaart%2C+Robert%22">Ietswaart, Robert</searchLink><relatesTo>3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Sengupta%2C+Shreoshi%22">Sengupta, Shreoshi</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ya%2C+VanNashlee%22">Ya, VanNashlee</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Aluya%2C+Chrystal%22">Aluya, Chrystal</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Fahey%2C+Caroline+G%22">Fahey, Caroline G</searchLink><relatesTo>1,2,3,5</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Louie%2C+Sharon+M%22">Louie, Sharon M</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Paschini%2C+Margherita%22">Paschini, Margherita</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kim%2C+Carla+F%22">Kim, Carla F</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<i> carla.kim@childrens.harvard.edu</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22EMBO+Journal%22">EMBO Journal</searchLink>. Jul2024, Vol. 43 Issue 14, p2843-2861. 19p. – Name: Subject Label: Subject Terms Group: Su Data: *<searchLink fieldCode="DE" term="%22LUNG+cancer%22">LUNG cancer</searchLink><br />*<searchLink fieldCode="DE" term="%22GENE+expression%22">GENE expression</searchLink><br />*<searchLink fieldCode="DE" term="%22PROGENITOR+cells%22">PROGENITOR cells</searchLink><br />*<searchLink fieldCode="DE" term="%22RAS+oncogenes%22">RAS oncogenes</searchLink><br />*<searchLink fieldCode="DE" term="%22GUANOSINE+triphosphatase%22">GUANOSINE triphosphatase</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Glycine-12 mutations in the GTPase KRAS (KRASG12) are an initiating event for development of lung adenocarcinoma (LUAD). KRASG12 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 KRASG12D mutation with temporal resolution. In AT2WT organoids, we found a transient injury/plasticity state preceding AT2 self-renewal and AT1 differentiation. Early-stage AT2KRAS cells exhibited perturbed gene expression dynamics, most notably retention of the injury/plasticity state. The injury state in AT2KRAS cells of patients, mice, and organoids was distinguishable from AT2WT states via altered receptor expression, including co-expression of ITGA3 and SRC. The combination of clinically relevant KRASG12D and SRC inhibitors impaired AT2KRAS 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. Synopsis: KRASG12 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. This study investigates the epigenetic and transcriptomic responses of AT2 cells to specific oncogenic events. AT2WT organoids adopt a transient, transitional injury/plasticity state prior to both AT2 self-renewal and AT1 differentiation. AT2KRAS cells co-opt and retain the transitional injury/plasticity state. AT2KRAS cells in patients, mice, and organoids differ from AT2WT cells by altered gene expression, including co-expression of ITGA3 and SRC. AT2KRAS cells in patients, mice, and organoids can be targeted using clinically-relevant KRASG12D and SRC inhibitors. KRASG12 mutations cause persistence of a normally transient injury/plasticity state in progenitor cells, leading to initiation of lung adenocarcinoma. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of EMBO Journal is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1038/s44318-024-00113-5 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 19 StartPage: 2843 Subjects: – SubjectFull: LUNG cancer Type: general – SubjectFull: GENE expression Type: general – SubjectFull: PROGENITOR cells Type: general – SubjectFull: RAS oncogenes Type: general – SubjectFull: GUANOSINE triphosphatase Type: general Titles: – TitleFull: Early-stage lung cancer is driven by a transitional cell state dependent on a KRAS-ITGA3-SRC axis. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Moye, Aaron L – PersonEntity: Name: NameFull: Dost, Antonella FM – PersonEntity: Name: NameFull: Ietswaart, Robert – PersonEntity: Name: NameFull: Sengupta, Shreoshi – PersonEntity: Name: NameFull: Ya, VanNashlee – PersonEntity: Name: NameFull: Aluya, Chrystal – PersonEntity: Name: NameFull: Fahey, Caroline G – PersonEntity: Name: NameFull: Louie, Sharon M – PersonEntity: Name: NameFull: Paschini, Margherita – PersonEntity: Name: NameFull: Kim, Carla F IsPartOfRelationships: – BibEntity: Dates: – D: 15 M: 07 Text: Jul2024 Type: published Y: 2024 Identifiers: – Type: issn-print Value: 02614189 Numbering: – Type: volume Value: 43 – Type: issue Value: 14 Titles: – TitleFull: EMBO Journal Type: main |
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