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Global transcriptomic changes in human lung fibroblasts MRC5 exposed to conditioned media from RAS-activated alveolar epithelial type II (ATII) cells based on RNA-seq.

ABSTRACT: IPF (idiopathic pulmonary fibrosis), a progressive lung disease with an unmet need for treatment, causes increased morbidity and mortality worldwide. Abnormal wound healing is strongly implicated in IPF, but the underlying mechanisms remain poorly understood. Here we reported that aberrant epithelial-mesenchymal crosstalk provides self-sustaining pro-fibrotic signals in IPF. By performing RNA-sequencing (RNA-seq) in human lung fibroblasts MRC5 treated with either conditioned media (CM) from control or 4-OHT (4-hydroxytamoxifen) - treated ATIIER:KRASV12 cells (kindly provided by Prof Julian Downward, The Francis Crick Institute, UK), in which addition of 4-OHT acutely activates RAS pathway (Yao et al. Cell Death & Differentiation 2019), we identify several IPF-related pathological alterations. These include increases in GO terms related to extracellular matrix (ECM) and collagen, cell migration, and inflammatory response. Our data suggest that RAS-activated ATII cells crosstalk to MRC5 lung fibroblasts to augment their activation and migration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163908 | GEO | 2021/08/09

REPOSITORIES: GEO

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Project description:We have developed cdk4/hTERT-immortalized normal human bronchial epithelial cells (HBECs) to study lung cancer pathogenesis. By studying the oncogenic effect of common lung cancer alterations (p53, KRAS, and c-MYC) we demonstrate the ability of this model to characterize the stepwise transformation of bronchial epithelial cells to full malignancy. Using HBECs derived from multiple individuals we found: 1) the combination of five genetic alterations (p53, KRASV12, c-MYC, CDK4 and hTERT) is sufficient for full tumorigenic conversion of HBECs; 2) high levels of KRASV12 are required for full malignant transformation of HBECs, however these levels also stimulate oncogene-induced senescence; 3) RAS-induced senescence is largely bypassed with loss of p53 function; 4) over-expression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; 5) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; 6) serum-induced epithelial-to-mesenchymal transition (EMT) increases in vivo tumorigenicity; 7) genetically-identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation as well as sensitivity to standard platinum-based chemotherapies; and 8) an mRNA signature derived from tumorigenic and non-tumorigenic clones is predictive of outcome in lung cancer patients. Collectively, we demonstrate this HBEC model system can be used to study the effect of oncogenic mutations on malignant progression, oncogene-induced senescence, and EMT along with clinically translatable applications such as development of prognostic signatures and drug response phenotypes. Human bronchial epithelial cells (HBECs) immortalized with cdk4 and hTERT were transformed with p53 knockdown, KrasV12 and cMYC over-expression and profiled on Illumina HumanHT-12 V4.0 expression beadchips. Transformed HBECs were grown in two different growth media: KSFM (defined, serum-free medium) or R10 (RPMI with 10% FBS) as indicated. Clones were isolated from HBECs with sh-p53 + KrasV12 and sh-p53 + KrasV12 + cMYC.

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Global transcriptomic changes in human lung fibroblasts MRC5 exposed to conditioned media from RAS-activated alveolar epithelial type II (ATII) cells based on RNA-seq.

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