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A non-genetic, cell cycle-dependent mechanism of platinum resistance in lung adenocarcinoma.

ABSTRACT: We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here, we advanced this model system and identified a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single-cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in human lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.

SUBMITTER: Gonzalez Rajal A

PROVIDER: S-EPMC8169122 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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A non-genetic, cell cycle-dependent mechanism of platinum resistance in lung adenocarcinoma.

Gonzalez Rajal Alvaro A Marzec Kamila A KA McCloy Rachael A RA Nobis Max M Chin Venessa V Hastings Jordan F JF Lai Kaitao K Kennerson Marina M Hughes William E WE Vaghjiani Vijesh V Timpson Paul P Cain Jason E JE Watkins D Neil DN Croucher David R DR Burgess Andrew A

eLife 20210513

We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here, we advanced this model system and identified a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single-cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain prolife ...[more]

PMID: 33983115

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Project description:The purpose of this study was to explore platinum resistance-related biomarkers and mechanisms in lung adenocarcinoma. Through the analysis of gene expression data of lung adenocarcinoma patients and normal patients from The Cancer Genome Atlas, Gene Expression Omnibus database, and A database of genes related to platinum resistance, platinum resistance genes in lung adenocarcinoma and platinum resistance-related differentially expressed genes were obtained. After screening by a statistical significance threshold, a total of 252 genes were defined as platinum resistance genes with significant differential expression, of which 161 were up-regulated and 91 were down-regulated. The enrichment results of up-regulated gene Gene Ontology (GO) showed that TOP3 entries related to biological processes (BP) were double-strand break repair, DNA recombination, DNA replication, the down-regulated gene GO enriches the TOP3 items about biological processes (BP) as a response to lipopolysaccharide, muscle cell proliferation, response to molecule of bacterial origin. Gene Set Enrichment Analysis showed that the top three were e2f targets, g2m checkpoint, and rgf beta signaling. A prognostic model based on non-negative matrix factorization classification showed the characteristics of high- and low-risk groups. The prognostic model established by least absolute shrinkage and selection operator regression and risk factor analysis showed that genes such as HOXB7, NT5E, and KRT18 were positively correlated with risk score. By analyzing the differences in m6A regulatory factors between high- and low-risk groups, it was found that FTO, GPM6A, METTL3, and YTHDC2 were higher in the low-risk group, while HNRNPA2B1, HNRNPC, TGF2BP1, IGF2BP2, IGF2BP3, and RBM15B were higher in the high-risk group. Immune infiltration and drug sensitivity analysis also showed the gene characteristics of the platinum-resistant population in lung adenocarcinoma. ceRNA analysis showed that has-miR-374a-5p and RP6-24A23.7 were lower in the tumor expression group, and that the survival of the low expression group was worse than that of the high expression group. In conclusion, the results of this study show that platinum resistance-related differentially expressed genes in lung adenocarcinoma are mainly concentrated in biological processes such as DNA recombination and response to lipopolysaccharide. The validation set proved that the high-risk group of our prognostic model had poor survival. M6A regulatory factor analysis, immune infiltration, and drug sensitivity analysis all showed differences between high and low-risk groups. ceRNA analysis showed that has-miR-374a-5p and RP6-24A23.7 could be protective factors. Further exploration of the potential impact of these genes on the risk and prognosis of drug-resistant patients with lung adenocarcinoma would provide theoretical support for future research.

Project description:BackgroundIdentified as a hallmark of cancer, the dysregulated cell cycle progression plays an important role in the promotion and progression of lung adenocarcinoma (LUAD). However, the genomic and microenvironment differences between cell cycle progression pathway altered/non-altered LUAD patients remain to be elucidated.Materials and methodsData of this study were obtained from The Cancer Genome Atlas (TCGA), including simple nucleotide variation, copy number variation (CNV), RNA-seq gene expression, miRNA expression, survival, and clinical information. Besides, 34 LUAD samples from our institution were used as a validation cohort. Differentially expressed genes (DEGs), enrichment analysis, and immune cell infiltration were detected. At last, we built a LASSO-binary Logistic regression model to predict the cell-cycle-related gene mutation (CDKN2A, CCND1, CDK4, CCNE1, and RB1) in LUAD patients and further verified it in the samples from our institution.ResultsBased on the cell cycle progression pathway status, the LUAD patients were divided into the mutation (n=322) and wild (n=46) groups. Compared to the wild group, the mutation group had a higher mutational load and CNV. Among the 16684 protein-coding genes analyzed, 302 were upregulated, and 354 were downregulated in the mutation group. Enrichment analysis indicated that these DEGs were closely related to metabolism items. After performing immune cell infiltration analysis of 22 immune cells, we found the proportion of 5 immune cells such as monocytes (P<0.01) and dendritic cells (P<0.01) were higher in the wild group. Finally, a cell-cycle-related 15-signature model was built by LASSO-Logistic regression analysis, which could predict the cell cycle progression pathway-related gene mutation (CDKN2A, CCND1, CDK4, CCNE1, and RB1) in LUAD patients. The validation cohorts showed the sensitivity and specificity of this model were 0.667 and 0.929, respectively.ConclusionThe genomic and microenvironment characteristics differed between the cell cycle progression pathway altered/non-altered patients with LUAD. Our findings may provide new insight into personalized treatment for LUAD patients.

Dataset Information

A non-genetic, cell cycle-dependent mechanism of platinum resistance in lung adenocarcinoma.

Publications

A non-genetic, cell cycle-dependent mechanism of platinum resistance in lung adenocarcinoma.

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