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

Aaron L Moye; Antonella Fm Dost; Robert Ietswaart; Shreoshi Sengupta; VanNashlee Ya; Chrystal Aluya; Caroline G Fahey; Sharon M Louie; Margherita Paschini; Carla F Kim

doi:10.1038/s44318-024-00113-5

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

EMBO J. 2024 May 16. doi: 10.1038/s44318-024-00113-5. Online ahead of print.

Authors

Aaron L Moye^{1

2

3}, Antonella Fm Dost^{1

2

3

4}, Robert Ietswaart³, Shreoshi Sengupta^{1

2

3}, VanNashlee Ya^{1

2

3}, Chrystal Aluya^{1

2

3}, Caroline G Fahey^{1

2

3

5}, Sharon M Louie^{1

2

3}, Margherita Paschini^{1

2

3}, Carla F Kim^{6

7

8}

Affiliations

¹ Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.
² Harvard Stem Cell Institute, Cambridge, MA, USA.
³ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁴ Hubrecht Institute, Oncode Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, The Netherlands.
⁵ Harvard University and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA. carla.kim@childrens.harvard.edu.
⁷ Harvard Stem Cell Institute, Cambridge, MA, USA. carla.kim@childrens.harvard.edu.
⁸ Department of Genetics, Harvard Medical School, Boston, MA, USA. carla.kim@childrens.harvard.edu.

PMID: 38755258
DOI: 10.1038/s44318-024-00113-5

Abstract

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.

Keywords: AT2; Adenocarcinoma; Cell States; KRAS; Lung.

Abstract

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