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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]

In the last decade, the generation and maintenance of organotypic structures has been propelled to the center stage of biomedical research. In the lung, a variety of protocols has been devised to generate organoids mimicking lung structures, but most methods with human cells have complicated lengthy protocols or a progressive decline in differentiation potential and physiological function with increasing passaging. A new study from Sachs et al () seeks to solve these issues, providing a versatile methodology to efficiently isolate, indefinitely culture, and manipulate human airway organoids, potentially allowing the in vitro modeling of a plethora of lung diseases. A new methods resource reports long‐term propagation of human lung epithelium as three dimensional organoids which can be exploited for disease modeling. [ABSTRACT FROM AUTHOR]

Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells ( TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24-dependent and Yap/ Taz-dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease. [ABSTRACT FROM AUTHOR]