DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a smoking-associated malignancy index

Su, Sheng‐Fang; Ho, Hao; Li, Jia Hua; Wu, Ming; Wang, Hsu Chieh; Yeh, Hsiang Yuan; Kuo, Sy‐Yen; Chen, Huei‐Wen; Ho, Chao‐Chi; Li, Ker Chau

doi:10.1172/jci139552

Cited by 8 publications

(8 citation statements)

References 63 publications

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“…Also, other researchers have reported that DNA methylation is associated with cigarette smoking [ 34 – 37 ], and changing the methylation in one CpG could induce gene expression [ 38 ]. Thus, due to the involvement of CS in alteration of DNA methylation status [ 39 , 40 ], and in hampering the expression of EYA4 in lung tissues taken from smokers compared to nonsmokers [ 27 ] as well as the impact of DNA methylation in depleting EYA4 expression in oral [ 41 ] and colon cancer [ 31 ], we suggest that CS could have a role in changing the methylation status of EYA4 in Saudi population.…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Regulates the Expression of EYA4 via Alternation of DNA Methylation Status

Almutairi

Alrefaei

et al. 2022

BioMed Research International

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Cigarette SMOKE (CS) considerably contributes to causing some diseases such as cancer, and it has a role in the alternation of gene expression through several mechanisms including epigenetics modification, particularly DNA methylation. EYA4 is one of the genes, that whose expression has been dysregulated in lung, colon, bladder, and breast cancer, leading to tumor progression. The alternation of DNA methylation levels has been implicated in regulating the expression of the EYA4 gene. Thus, in this study, we have shown the effect of CS on the DNA methylation level of the EYA4 promoter region as well as the methylation level on EYA4 expression. To determine the level of DNA methylation on the promoter region of the EYA4 gene, we have employed the bisulfite conversion treatment followed by the Sanger Sequence for 100 DNA samples taken from Saudi people (50 smokers and 50 nonsmokers). We found that 26% of DNA extracted from smoker samples is methylated, while there was no methylation identified in nonsmoker samples. Also, using the demethylating agents such as AZA on LoVo and Caco-2 cancer cell lines causes induction of transcription level of EYA4, implying the possible mechanism of DNA methylation in the upregulation of EYA4. These findings suggest the possible mechanism of CS in controlling the expression of EYA4 via changing the status of DNA methylation.

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Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Regulates the Expression of EYA4 via Alternation of DNA Methylation Status

Almutairi

Alrefaei

et al. 2022

BioMed Research International

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“…With regard to the effect of CAF heterogeneity on the "methylome", Su et al . constructed a methylation index (MIND) for NF/CAF discrimination in NSCLC (Su et al 2021 ). MIND was based on 54 smoking-associated CpG sites and was suggested to reflect the malignancy of the TME and predict patient survival.…”

Section: Tumor Fibrosismentioning

confidence: 99%

“…The mechanism contributing to the phenotypic and functional heterogeneity among fibroblasts remains an issue in the lung cancer field. Emerging data on the functional heterogeneity of CAFs in lung cancer have started to appear (Su et al 2018 , 2021 ; Hao et al 2019 ; Hu et al 2021 ). Using bulk RNA-seq TCGA data, Dominguez et al .…”

Section: Tumor Fibrosismentioning

confidence: 99%

“…In a separate study, Sato et al showed that TGF-β1 released by α-SMA + mouse CAF induced morphological changes and gene expression of the tumor cells, thus may contribute to the histological heterogeneity of lung adenocarcinoma (Sato et al 2021). With regard to the effect of CAF heterogeneity on the "methylome", Su et al constructed a methylation index (MIND) for NF/CAF discrimination in NSCLC (Su et al 2021). MIND was based on 54 smoking-associated CpG sites and was suggested to reflect the malignancy of the TME and predict patient survival.…”

Section: Recent Developments In Lung Cancer Cafsmentioning

confidence: 99%

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Integrin α11β1 in tumor fibrosis: more than just another cancer-associated fibroblast biomarker?

Zeltz

Navab

Heljasvaara

et al. 2022

J. Cell Commun. Signal.

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There is currently an increased interest in understanding the role of the tumor microenvironment (TME) in tumor growth and progression. In this context the role of integrins in cancer-associated fibroblasts (CAFs) will need to be carefully re-evaluated. Fibroblast-derived cells are not only in the focus in tumors, but also in tissue fibrosis as well as in inflammatory conditions. The recent transcriptional profiling of what has been called “the pan-fibroblast cell lineage” in mouse and human tissues has identified novel transcriptional biomarker mRNAs encoding the secreted ECM proteins dermatopontin and collagen XV as well as the phosphatidylinositol-anchored membrane protein Pi16. Some of the genes identified in these fibroblasts scRNA-seq datasets will be useful for rigorous comparative characterizations of fibroblast-derived cell subpopulations. At the same time, it will be a challenge in the coming years to validate these transcriptional mRNA datasets at the protein-(expression) and at tissue-(distribution) levels and to find useful protein biomarker reagents that will facilitate fibroblast profiling at the cell level. In the current review we will focus on the role of the collagen-binding integrin α11β1 in CAFs, summarizing our own work as well as published datasets with information on α11 mRNA expression in selected tumors. Our experimental data suggest that α11β1 is more than just another biomarker and that it as a functional collagen receptor in the TME is playing a central role in regulating collagen assembly and matrix remodeling, which in turn impact tumor growth and metastasis.

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“…This similarity was in contrast to the organ-dependent transcriptomic difference of normal fibroblasts. Recently, genome-wide DNA methylation and gene expression profiling of lung CAFs and patient-matched NFs identified a methylation index of 54 CpG sites for CAF/NF discrimination [33]. Of clinical importance, this methylation index could stratify the malignant status of the tumor microenvironment among different patients and serve as a biomarker to predict recurrence in multiple lung cancer cohorts.…”

Section: Diversity and Organ Specificity Of Fibroblastsmentioning

confidence: 99%

Organ Specificity and Heterogeneity of Cancer-Associated Fibroblasts in Colorectal Cancer

Miyashita

Saito

2021

IJMS

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Fibroblasts constitute a ubiquitous mesenchymal cell type and produce the extracellular matrix (ECM) of connective tissue, thereby providing the structural basis of various organs. Fibroblasts display differential transcriptional patterns unique to the organ of their origin and they can be activated by common stimuli such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) signaling. Cancer-associated fibroblasts (CAFs) reside in the cancer tissue and contribute to cancer progression by influencing cancer cell growth, invasion, angiogenesis and tumor immunity. CAFs impact on the tumor microenvironment by remodeling the ECM and secreting soluble factors such as chemokines and growth factors. Differential expression patterns of molecular markers suggest heterogeneous features of CAFs in terms of their function, pathogenic role and cellular origin. Recent studies elucidated the bimodal action of CAFs on cancer progression and suggest a subgroup of CAFs with tumor-suppressive effects. This review attempts to describe cellular features of colorectal CAFs with an emphasis on their heterogeneity and functional diversity.

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DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a smoking-associated malignancy index

Cited by 8 publications

References 63 publications

Cigarette Smoke Regulates the Expression of EYA4 via Alternation of DNA Methylation Status

Cigarette Smoke Regulates the Expression of EYA4 via Alternation of DNA Methylation Status

Integrin α11β1 in tumor fibrosis: more than just another cancer-associated fibroblast biomarker?

Organ Specificity and Heterogeneity of Cancer-Associated Fibroblasts in Colorectal Cancer

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