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Gramd2+ alveolar type I cells can give rise to Kras-induced lung adenocarcinoma

ABSTRACT: Gramd2+ alveolar type I cells can give rise to Kras-induced lung adenocarcinoma

PROVIDER: PRJNA891038 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21922523.fastq.gz	Fastqsanger.gz
	SRR21922524.fastq.gz	Fastqsanger.gz
	SRR21922525.fastq.gz	Fastqsanger.gz
	SRR21922526.fastq.gz	Fastqsanger.gz
	SRR21922527.fastq.gz	Fastqsanger.gz

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Gramd2+ alveolar type I cells can give rise to Kras-induced lung adenocarcinoma

Project description:Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and arises in the distal lung. LUAD encompasses several pathologic subtypes, including solid, lepidic, papillary, micropapillary, acinar and mixed subtypes, each with differing clinical outcomes or biological behavior. Specifically, lepidic histology is associated with improved survival relative to other LUAD histologies. Yet, the molecular and cellular underpinnings of these subtypes are largely unknown. Understanding which cell populations in the distal lung contribute to LUAD could provide insights for the marked heterogeneity in LUAD pathologic features, clinical presentation and responses to therapy.Recent studies have seen tumor-derived epithelial cells with an AT1 transcriptomic cell signature, suggesting AT1 cells may contribute to a subset of LUAD cases. We tested the ability of AT1 cells to give rise to LUAD by inducing KrasG12D, a known oncogenic driver in human LUAD. Activation of KrasG12D in Gram-domain containing 2 (Gramd2)+ AT1 cells gave rise to multiple LUAD lesions, primarily of papillary histology. In contrast, activation of KrasG12D in Sftpc+ AT2 cells resulted in LUAD lesions of lepidic histology. Immunohistochemistry established Gramd2:KrasG12D lesions were of primary lung origin and not metastatic events. Spatial transcriptomic profiling revealed distinct pathway alterations occurring within Gramd2- and Sftpc-derived LUAD. Immunofluorescence confirmed differences observed in the Spatial transcriptomic analysis in expression patterns and distribution of cell-specific markers between cell of origin, while universal upregulation of the Krt8 intermediate cell state marker was observed. Our results are consistent with Gramd2+ AT1 cells serving as a putative cell of origin for LUAD and suggest that LUAD may be a collection of adenocarcinomas that share a common location within the distal lung, but which arise from different cells of origin.

2022-10-19 | GSE215858 | GEO

Alveolar type I cells can give rise to KRAS-induced lung adenocarcinoma.

Project description:Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

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Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma [RNA-seq]

Project description:Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intra-tumoral heterogeneity and suggest targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.

2023-11-01 | GSE246480 | GEO

Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma [scRNA-seq]

2023-11-01 | GSE246481 | GEO

Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma

Project description:Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma

| PRJNA1033182 | ENA

Human hepatocytes can give rise to intrahepatic cholangiocarcinomas

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Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma [RNA-seq]

Project description:Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma [RNA-seq]

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Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma [scRNA-seq]

Project description:Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma [scRNA-seq]

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Understanding transcriptional profile of alveolar Type I, Type II and double positive (Type I/II+) cells upon KrasG12D activation in mouse lungs during lung adenocarcinoma.

Project description:Previously, we identifed alveolar Type II cells as cell-of-origin for Kras induced lung adenocarcinoma. In the current study, we examined the phenotype of Type II cells after Kras activation and found evidence for proliferation of cells that co-express Type I and Type II markers. Using RNAseq, we are trying to charcterize these different alveolar epithelial cells (Type I, Type II and double positive (Type I/II+)) upon KrasG12D activation during lung adenocarcinoma.

2023-05-09 | GSE230664 | GEO

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