Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells

Dost, Antonella F M; Moye, Aaron L.; Vedaie, Marall; Tran, Linh M.; Fung, Eileen; Heinze, Dar; Villacorta‐Martin, Carlos; Huang, Jessie; Hekman, Ryan; Kwan, Julian; Blum, Benjamin; Louie, Sharon M.; Rowbotham, Samuel P.; Aja, Julio Sainz de; Piper, Mary E.; Bhetariya, Preetida J.; Bronson, Roderick T.; Emili, Andrew; Mostoslavsky, Gustavo; Fishbein, Gregory A.; Wallace, W. Dean; Krysan, Kostyantyn; Dubinett, Steven M.; Yanagawa, Jane; Kotton, Darrell N.; Kim, Carla F.

doi:10.1016/j.stem.2020.07.022

Cited by 97 publications

(113 citation statements)

References 95 publications

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“…While the alveolar differentiation marker SPC was uniformly expressed in SOX9-IAC, its downregulation coincided with the appearance of papillary tissue structure, and SPC was completely absent in mature SOX9-expressing papillary tumour regions. A transition from alveolar dedifferentiation to gradual SOX9 expression was similarly seen following oncogenic KRAS expression in organoids [34], and corroborates data showing that ectopic expression of SOX9 in embryonic lungs prevented AT2 cell differentiation [12,13], overall indicating that SOX9 expression intrinsically associates with AT2 lineage exit. Use of a conditional Sox9 null model to address the role of SOX9 in NSCLC progression showed that Sox9 loss disrupted the formation of PAC and papillary AC cores of ASC lesions, but not IAC or histotypes derived from bronchial progenitors.…”

Section: Discussionsupporting

confidence: 77%

The role of SOX9 in non-small cell lung cancer progression is histopathology-selective

Bao

Närhi

Teodósio

et al. 2020

Preprint

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The transcription factor SOX9 is a key regulator of multiple developmental processes, and is frequently re-expressed in non-small cell lung cancer (NSCLC). Its precise role in the progression of NSCLC histopathologies has however remained elusive. We show that SOX9 expression relates to poor outcome and invasive histopathology in human adenocarcinomas, and is absent in murine early minimally invasive and human in situ adenocarcinoma. Interestingly, despite wide SOX9 expression across advanced NSCLC histotypes, its genetic deletion in the murine KrasG12D;Lkb1-/- model selectively disrupted only the growth of papillary NSCLC, without affecting the initiation of precursor lesions or growth of mucinous or squamous tissue. Spatial tissue phenotyping indicated a requirement of SOX9 expression for the progression of surfactant protein C-expressing progenitor cells, which gave rise to papillary tumours. Intriguingly, while SOX9 expression was dispensable for squamous tissue formation, its loss in fact led to enhanced squamous tumour metastasis, which was associated with altered collagen IV deposition in the basement membrane. Our work therefore demonstrates histopathology-selective roles for SOX9 in NSCLC progression, namely a requirement for papillary adenocarcinoma progression, but opposing metastasis-suppressing function in squamous histotype tissue. This attests to a pleiotropic SOX9 function, linked to the cell of origin and microenvironmental tissue contexts.

show abstract

Section: Discussionsupporting

confidence: 77%

The role of SOX9 in non-small cell lung cancer progression is histopathology-selective

Bao

Närhi

Teodósio

et al. 2020

Preprint

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“…Organotypic 3D cultures, organon-a-chip, and precision-cut lung slices are now reliable tools that provide the environment required to maintain and study AT2 cells and other epithelial progenitor cells. They can be used in various settings, from understanding developmental processes to disease modeling and drug testing (13)(14)(15)(16)(17). These new tools offer great promise for broad applications.…”

mentioning

confidence: 99%

Repurposing A549 Adenocarcinoma Cells: New Options for Drug Discovery

Alba

2021

Am J Respir Cell Mol Biol

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“…There is no gold standard to evaluate the estimated changing expression levels. Despite the two obstacles, RNA velocity has proved its usefulness to estimate transcriptional changes of genes in many applications [22,23].…”

Section: Discussionmentioning

confidence: 99%

Inferring time-lagged causality using the derivative of single-cell expression

Wei

Zhao

2021

Preprint

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Many computational methods have been developed for inferring causality among genes using cross-sectional gene expression data, such as single-cell RNA sequencing (scRNA-seq) data. However, due to the limitations of scRNA-seq technologies, time-lagged causal relationships may be missed by existing methods. In this work, we propose a method, called causal inference with time-lagged information (CITL), to infer time-lagged causal relationships from scRNA-seq data by assessing conditional independence between the changing and current expression levels of genes. CITL estimates the changing expression levels of genes by "RNA velocity". We demonstrate the accuracy and stability of CITL for inferring time-lagged causality on simulation data against other leading approaches. We have applied CITL to real scRNA data and inferred 878 pairs of time-lagged causal relationships, with many of these inferred results supported by the literature.

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Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells

Cited by 97 publications

References 95 publications

The role of SOX9 in non-small cell lung cancer progression is histopathology-selective

The role of SOX9 in non-small cell lung cancer progression is histopathology-selective

Repurposing A549 Adenocarcinoma Cells: New Options for Drug Discovery

Inferring time-lagged causality using the derivative of single-cell expression

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