Cancer evolution and heterogeneity

Mimori, Koshi; Saito, Tomoko; Niida, Atsushi; Miyano, Satoru

doi:10.1002/ags3.12182

Cited by 20 publications

(19 citation statements)

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“…Although mutational evolutionary analyses are providing important insights into the clonal (gene-based) divergences associated with tissue dependent metastatic adaptation(s) (evolution) [9,11,[44][45][46], as previously reported and expanded upon here, our isogenic model system has revealed isogenic cell line specific pathways that indeed have been influenced by the microenvironment of the cell line's organ of origin. Examples have been pointed out in the Results section (Tables 1-6).…”

Section: Plos Onementioning

confidence: 65%

Divergent organ-specific isogenic metastatic cell lines identified using multi-omics exhibit differential drug sensitivity

et al. 2020

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Background Monitoring and treating metastatic progression remains a formidable task due, in part, to an inability to monitor specific differential molecular adaptations that allow the cancer to thrive within different tissue types. Hence, to develop optimal treatment strategies for metastatic disease, an important consideration is the divergence of the metastatic cancer growing in visceral organs from the primary tumor. We had previously reported the establishment of isogenic human metastatic breast cancer cell lines that are representative of the common metastatic sites observed in breast cancer patients. Methods Here we have used proteomic, RNAseq, and metabolomic analyses of these isogenic cell lines to systematically identify differences and commonalities in pathway networks and examine the effect on the sensitivity to breast cancer therapeutic agents. Results Proteomic analyses indicated that dissemination of cells from the primary tumor sites to visceral organs resulted in cell lines that adapted to growth at each new site by, in part, acquiring protein pathways characteristic of the organ of growth. RNAseq and metabolomics analyses further confirmed the divergences, which resulted in differential efficacies to commonly used FDA approved chemotherapeutic drugs. This model system has provided data that indicates that organ-specific growth of malignant lesions is a selective adaptation and growth process. Conclusions The insights provided by these analyses indicate that the rationale of targeted treatment of metastatic disease may benefit from a consideration that the biology of metastases has diverged from the primary tumor biology and using primary tumor traits as the basis for treatment may not be ideal to design treatment strategies.

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Section: Plos Onementioning

confidence: 65%

Divergent organ-specific isogenic metastatic cell lines identified using multi-omics exhibit differential drug sensitivity

et al. 2020

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“…We speculated that radiation resistance caused by intratumoral heterogeneity led to tumor recurrence and progression. 35 To evaluate radiotherapy efficacy, Zhou reported that non-invasive MRI could monitor the physiological changes caused by radiotherapy. 36 However, there remained no convincing preclinical model to dynamically monitor the occurrence of radiation resistance.…”

Section: Discussionmentioning

confidence: 99%

Construction of Radiation Surviving/Resistant Lung Cancer Cell Lines with Equidifferent Gradient Dose Irradiation

Wang

Zhu

2020

Dose-Response

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Radiotherapy plays an increasingly crucial role in the treatment of non-small cell lung cancer (NSCLC). Local tumor recurrence and tumor progression caused by intratumoral heterogeneity induced radiotherapy resistance remain the primary causes of radiotherapy failure. However, the lack of a suitable cell line model has hampered the exploration of the dynamic mechanisms of radiation resistance. We established 3 groups of equidifferent gradient dose irradiation surviving/resistant human lung cancer cell lines based on A549, H520, and H460 cells with clinical conventional fractionated radiotherapy (CFRT) (2 Gy × 20 F, 2 Gy × 30 F, and 2 Gy × 40 F). The radiosensitivity of the cells was detected by clone formation assay, EDU cell proliferation assay, neutral comet assay, and γ-H2AX immunofluorescence staining. The radiosensitivity and proliferation viability were increased in a received dose-dependent manner. Compared with parental cells, DNA double-strand breaks (DSBs) in cell lines that received higher-dose irradiation were significantly reduced. We successfully constructed equidifferent gradient dose irradiation surviving/resistant NSCLC cell lines whose radiation surviving and resistant abilities were increased in a received dose-dependent manner. This preclinical cell model could be used to dynamically observe and detect the radiation surviving/resistant biomarkers during radiotherapy stress, elucidate the mechanism of radiation resistance.

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“…Since colorectal polyps and tumors are heterogeneous and multiclonal [15], and the Darwinian evolution of colorectal cancer starts from early adenomas [26], they are expected to show varying levels of expression for a specific gene. This justifies the very wide levels of expression of different genes in different biopsies; in our study more than 30 folds for PRKCQ-AS1 and more than 60 folds for SATB1-AS1 (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Our analysis of antisense gene expression in relation to mutations in sense genes and driver genes shows that the expression of PRKCQ-AS1 is not affected and deregulated when the sense gene (PRKCQ) or driver genes (APC, BRAF, TP53, PIK3CA, SMAD4, and EGFR) are mutated. By multi-region whole-exome sequencing, Mimori and colleagues [26] report that early tumors accumulate a higher proportion of subclonal driver mutations than the advanced tumors, and that the variant allele frequencies of subclonal mutations tend to be higher in early tumors. These authors suggest that the subclonal mutations are subject to selective sweep in early tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Expression profile analysis of two antisense lncRNAs to improve prognosis prediction of colorectal adenocarcinoma

et al. 2019

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BackgroundLong noncoding RNAs (lncRNAs) are involved in different pathogenesis pathways including cancer pathogenesis. The adenoma-carcinoma pathway in colorectal cancer may involve the aberrant and variable gene expression of regulatory RNAs. This study was conducted to analyse the expression and prognosis prediction ability of two natural antisense transcripts, protein kinase C theta antisense RNA 1 (PRKCQ-AS1), and special AT-rich sequence binding protein 1 antisense RNA 1 (SATB1-AS1) in colorectal low-grade adenoma, advanced adenoma, and adenocarcinomas.MethodsIn this study, from two RNA-seq analyses of CCAT1-ko cells and colorectal carcinoma biopsies having diminished and increased levels of CCAT1 transcription, respectively, we nominated two antisense lncRNAs of PRKCQ-AS1 and SATB1-AS1. Samples from colorectal low-grade adenomas, advanced adenomas, adenocarcinomas, and adjacent tissue were subjected to RT-qPCR to determine the expression of PRKCQ-AS1, SATB1-AS1 along with colon cancer-associated transcript 1 (CCAT1) and cMYC. In addition, we used different bioinformatics analyses and webservers (including GEPIA 2, TCGA, and CancerMine) to elucidate the prognosis prediction value, the expression correlation of sense–antisense pair of genes, and the expression profile of these antisense transcripts at the presence or absence of mutations in the driver genes, or the corresponding sense genes.ResultsPRKCQ-AS1 showed a wide range of expression levels in colorectal adenoma, advanced adenoma, and adenocarcinoma. Upregulation of PRKCQ-AS1 was related to a significant decrease in survival of colorectal cancer (CRC) patients. The expression levels of PRKCQ-AS1 and PRKCQ were strong and significantly concordant in normal and cancerous colorectal tissues. While SATB1-AS1 showed a wide range of expression in colorectal adenoma, advanced adenoma, and adenocarcinoma as well, its expression was not related to a decrease in survival of CRC patients. The expression levels of SATB1-AS1 and SATB1 (the sense gene) were not strong in normal colorectal tissues. In addition, where SATB1 gene was mutated, the expression of SATB1-AS1 was significantly downregulated.ConclusionsWe found the expression of PRKCQ-AS1 and SATB1-AS1 at a given stage of CRC very variable, and not all biopsy samples showed the increased expression of these antisense transcripts. PRKCQ-AS1 in contrast to SATB1-AS1 showed a significant prognostic value. Since a significantly concordant expression was observed for SATB1-AS1 and SATB1 in only cancerous, and for PRKCQ-AS1 and PRKCQ in both normal and cancerous colorectal tissues, it can be concluded that common mechanisms may regulate the expression of these sense and antisense genes.

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Cancer evolution and heterogeneity

Cited by 20 publications

References 50 publications

Divergent organ-specific isogenic metastatic cell lines identified using multi-omics exhibit differential drug sensitivity

Divergent organ-specific isogenic metastatic cell lines identified using multi-omics exhibit differential drug sensitivity

Construction of Radiation Surviving/Resistant Lung Cancer Cell Lines with Equidifferent Gradient Dose Irradiation

Expression profile analysis of two antisense lncRNAs to improve prognosis prediction of colorectal adenocarcinoma

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