Definitive evidence for Club cells as progenitors for mutant <i>Kras/Trp53</i>‐deficient lung cancer

The molecular heterogeneity of cancer cells contributes to the often partial response to targeted therapies and relapse of disease due to the escape of resistant cell populations. While single-cell sequencing has started to improve our understanding of this heterogeneity, it offers a mostly descriptive view on cellular types and states. To obtain more functional insights, we propose scGeneRAI, an explainable deep learning approach that uses layer-wise relevance propagation (LRP) to infer gene regulatory networks from static single-cell RNA sequencing data for individual cells. We benchmark our method with synthetic data and apply it to single-cell RNA sequencing data of a cohort of human lung cancers. From the predicted single-cell networks our approach reveals characteristic network patterns for tumor cells and normal epithelial cells and identifies subnetworks that are observed only in (subgroups of) tumor cells of certain patients. While current state-of-the-art methods are limited by their ability to only predict average networks for cell populations, our approach facilitates the reconstruction of networks down to the level of single cells which can be utilized to characterize the heterogeneity of gene regulation within and across tumors.

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“…This is consistent with the hypothesis that NSCLC cells origin from AT2 cells or secreting (e.g. club) cells ( 45–47 ).…”

Section: Resultssupporting

confidence: 92%

Single-cell gene regulatory network prediction by explainable AI

Keyl

Bischoff

Dernbach

et al. 2023

Nucleic Acids Research

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“…Remarkably, regardless of the originating cell type, all Eml4-Alk tumours were positive for the AT2 cell marker, SPC. In line with this observation, Rosigkeit et al 28 have recently shown that Club-originated tumours become AT2-like by expressing SPC. DNA methylation was shown to act as cellular memory, storing information on previous differentiation states 37 .…”

Section: Discussionmentioning

confidence: 56%

“…At the early stages of tumorigenesis, Eml4-Alk induced early hyperplasia in the bronchi that partially lost the Club cell marker CCSP, and acquired alveolar markers such as SPC, similar to Kras mutant LUAD, described by the authors in ref. 28 (Fig. 1b, c ).…”

Section: Resultsmentioning

confidence: 92%

“…We showed that due to the high plasticity of lung epithelial cells, tumour characteristics are only partly dependent on their originating cell type. Previous studies focused on defining the cellular origin of LUAD, by using Kras mutant models that were based on tumour induction in specific cell types 21 – 23 , 26 , 28 , 56 . We studied the cell of origin of Eml4-Alk LUAD using a stochastic adenoviral system and employed lineage-tracing mouse models to label Club, AT2, AT1, Ciliated and Basal cells.…”

Section: Discussionmentioning

confidence: 99%

“…Employing engineered reporters together with toxic chemicals found in tobacco smoke, we proved that tobacco-induced tumours originate from airway epithelial cells, which attain alveolar characteristics, and not exclusively from cells originating in the alveoli 26 . In addition, two recent papers showed that mutant Kras expressed in Club cells induces LUAD in mice 27 , 28 . Altogether, these studies suggest that Club cells give rise to oncogene and chemical-induced LUAD by attaining an AT2 phenotype; however, there is a general lack of knowledge of the developmental routes and pathways that Club cells use to become a tumour.…”

Section: Introductionmentioning

confidence: 99%

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Club cells employ regeneration mechanisms during lung tumorigenesis

et al. 2022

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The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we employ lineage-tracing mouse models to investigate the cell of origin of Eml4-Alk LUAD, and show that Club and Alveolar type 2 (AT2) cells give rise to tumours. We focus on Club cell originated tumours and find that Club cells experience an epigenetic switch by which they lose their lineage fidelity and gain an AT2-like phenotype after oncogenic transformation. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, suggesting that lung epithelial cells leverage on their plasticity and intrinsic regeneration mechanisms to give rise to a tumour. Together, this study highlights the role of Club cells in LUAD initiation, identifies the mechanism of Club cell lineage infidelity, confirms the presence of these features in human tumours, and unveils key mechanisms conferring LUAD heterogeneity.

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Macrophage migration inhibitory factor may contribute to the occurrence of multiple primary lung adenocarcinomas

Liu,

Yang,

Zhi

et al. 2023

Clinical & Translational Med

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BackgroundThis study aimed to identify the key genes involved in the development of multiple primary lung cancers.MethodsDifferential expression analysis was performed, followed by comparing the infiltration levels of 22 immune cell types between multiple and single primary lung adenocarcinomas. Marker genes for epithelial cells with different proportions between the two types of lung adenocarcinomas were identified. The common genes between the marker genes and differentially expressed genes were identified. Finally, the effects of the key genes were tested on the in vitro proliferation, migration and morphology.Results:The infiltration levels of helper follicular T cells, resting NK cells, activated NK cells, M2 macrophages and resting mast cells were higher in the patients with multiple than in those with single primary lung adenocarcinomas. A total of 1553 differentially expressed genes and 4414 marker genes of epithelial cells were identified. Logistic regression analysis was performed on the 164 resulting genes. The macrophage migration inhibitory factor expression was positively associated with the occurrence of multiple primary lung adenocarcinomas. Moreover, its signalling pathway was the key pathway among the epithelial cells and multiple and single primary lung adenocarcinoma cells, and it was upregulated in lung adenocarcinoma cells. It also increased the expression of lung cancer markers, including NES and CA125, induced morphological changes in alveolar epithelial type II cells, and promoted their proliferation, migration and invasion.ConclusionsMultiple and single primary lung adenocarcinomas have different tumour immune microenvironments, and migration inhibitory factor may be a key factor in the occurrence of multiple primary lung adenocarcinomas.

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Definitive evidence for Club cells as progenitors for mutant Kras/Trp53‐deficient lung cancer

Cited by 5 publications

References 62 publications

Single-cell gene regulatory network prediction by explainable AI

Single-cell gene regulatory network prediction by explainable AI

Club cells employ regeneration mechanisms during lung tumorigenesis

Macrophage migration inhibitory factor may contribute to the occurrence of multiple primary lung adenocarcinomas

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