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Sustained NF-kB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation [Expt2]

ABSTRACT: Tissue homeostasis relies on meticulously coordinated fate determination by resident stem cells through a tissue-wide feedback loop. Dysregulation of this process is closely associated with tumorigenesis, yet the mechanisms distinguishing these phenomena remain in question. Here, we integrate comparative analyses of in vivo large-scale quantitative clonal dynamics and single-cell transcriptomics to unveil a key evolutionary trajectory within a single alveolar type II (AT2) stem cell, driving tissue-wide neoplastic transformation in the lung. Tracking thousands of AT2 clones throughout murine adulthood uncovers two independent homeostatic AT2 subpopulation scharacterised by unique cellular kinetics. Notably, a small AT2 subset undergoes substantial clonal expansion upon KrasG12D activation. The mutant AT2 cells follow a differentiation trajectory via emergent regenerative cell states, yet exhibit remarkable cell state equivalency with stochastic fate transitions, driving abnormal expansion with halted differentiation into mature AT1 cells. The genetic deletion of Il1r1 signalling impedes oncogenic expansion by disrupting this reprogramming trajectory, underscoring its significance in tumour initiation. Significantly, our analysis of oncogene-associated multi-colour reporter mouse models reveals a tissue- wide systemic injury response elicited by oncogenic clones in neighbouring wildtype AT2 cells, modulating their fitness programme. Moreover, we identify sustained NF-kB activation in reprogrammed cell states, setting neoplastic transformation apart from normal regeneration by preventing oncogenic exit into the differentiated AT1 state. Collectively, this work delineates the common mechanisms governing lineage infidelity across diverse tissues and proposes a compelling target amenable to therapeutic manipulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE247504 | GEO | 2025/02/19

REPOSITORIES: GEO

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Project description:Alveoli are thin-walled sacs that serve as the gas exchange units of the lung. They are affected in devastating lung diseases including COPD, Idiopathic Pulmonary Fibrosis, and the major form (adenocarcinoma) of lung cancer, the leading cause of cancer deaths. The alveolar epithelium is composed of two morphologically distinct cell types: alveolar type (AT) 1 cells, exquisitely thin cells across which oxygen diffuses to reach the blood, and AT2 cells, specialized surfactant-secreting cells. Classical studies suggested that AT1 cells arise from AT2 cells during development and following injury, but more recent studies suggest other sources. Here we use histological and marker analysis, lineage tracing, and clonal analysis in mice to identify alveolar progenitor and stem cells and map their locations and potential in vivo. The results show that AT1 and AT2 cells arise independently during development from a bipotential progenitor. After birth, new AT1 cells derive from rare, long-lived, self-renewing AT2 cells, each producing a slowly expanding clonal focus of regenerated alveoli contiguous with the founder AT2 cell. This stem cell function of AT2 cells is broadly activated by diffuse AT1 cell injury, and AT2 self-renewal can be induced in vitro by EGF ligands and permanently activated in vivo by AT2 cell-specific targeting of the oncogenic KrasG12D allele, efficiently transforming AT2 cells into monoclonal adenomatous tumors that rapidly enlarge and prove fatal. Thus, there is a developmental switch in alveolar progenitor cells after birth, when mature AT2 cells function as facultative stem cells that contribute to local alveolar renewal, repair, and cancer. We propose that short-range signals from dying AT1 cells regulate AT2 stem cell activity: a signal transduced by EGFR-KRAS controls AT2 self-renewal and is hijacked during oncogenic transformation, and a separate signal controls reprogramming to AT1 cell fate. To compare expression between ATII and E18 BP populations, RNA was isolated from either population purified by FACS. Two populations are analyzed with 3 biological replicates per population.

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Sustained NF-kB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation [Expt2]

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