Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD‐L1)‐mediated immunosuppression

Xu, Qixia; Long, Qilai; Zhu, Dexiang; Fu, Da; Zhang, Boyi; Liu, Han; Qian, Min; Guo, Jianming; Xu, Jianmin; Cao, Liu; Chin, Y. Eugene; Coppé, Jean‐Philippe; Lam, Eric; Campisi, Judith; Sun, Yu

doi:10.1111/acel.13027

Cited by 101 publications

(105 citation statements)

References 55 publications

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“…In our study, we further explored the methylation change of the previous screened aging-related genes in peripheral venous blood of asthma patients. Indeed, the involvement of these screened 9 aging-related genes in asthma have been extensively studied by previous literatures [42][43][44][45][46][47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Variable Expressed Methylation Sites of Aging-related Genes in Asthma

Yang¹,

Lin²,

Yang³

et al. 2020

Preprint

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Background: Asthma is a complex pulmonary inflammatory disease which is common in the elderly. Aging-related alterations have also been found in the structural cells and immune cells of asthma patients although the pathological mechanism of the differential aging-related gene in the development of asthma is still obscure. Of note, DNA methylation (DNAm) have been proven to play an important role in the regulation of aging-related genes. However, the methylation levels of aging-related genes in asthma patients are largely unclear.Methods: First, the mRNA levels and DNAm level of the previous screened 9 aging-related genes in peripheral blood of 51 healthy controls (HCs) and 55 asthmatic patients were detected by multiple targeted bisulfite enrichment sequencing (MethTarget) and qPCR. Secondly, the correlation between the DNAm level of specific altered CpG sites and the pulmonary function indicators of asthma patients was evaluated. Lastly, the Receiver Operator Characteristic (ROC) curve and Principal Component Analysis (PCA) were used to identify the feasibility of the candidate CpG sites as asthma markers.Results: The mRNA expression of the 9 aging-related gene in peripheral blood of asthma patients was significantly different from those of HCs. Besides, the methylation level of the 9 aging-related genes also altered in asthma patients, and a total of 68 CpG sites were related to the severity of asthma. Notably, 10 of the 68 CpG sites had a significant relationship with pulmonary function parameters. Moreover, ROC curve and PCA analysis showed that the candidate differential methylation sites (DMSs) can be used as potential biomarkers for asthma.Conclusions:In summary, this study confirmed the changes in the mRNA expression and DNAm level of aging-related genes in asthma patients. The differential DMSs are associated with the clinical evaluation indicators of asthma, which may indicate the involvement of aging-related genes in the pathogenesis of asthma and provide some new possible biomarker of asthma.

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Section: Discussionmentioning

confidence: 99%

Variable Expressed Methylation Sites of Aging-related Genes in Asthma

Yang¹,

Lin²,

Yang³

et al. 2020

Preprint

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“…7Eand Extended DataFig. 6B).However, these changes seem to be generally limited to stromal cells, rather than their adjacent epithelial cell counterparts, which have repopulated upon development of drug resistance in the course of treatment as previously characterized31,38 . We further assessed the in situ inducibility of KDM4A/B in tumor samples, and noticed substantial expression of these factors in animals experiencing MIT-involved treatments (Extended DataFig.…”

mentioning

confidence: 82%

KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype

Zhang

Long

et al. 2020

Preprint

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Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation, including epigenetic decoration of chromatin structure and functional modulation of bioactive components. Here we report that expression of the histone H3-specific demethylase KDM4 is upregulated in human stromal cells upon cellular senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation are correlated with adverse survival of cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq and expression profiling through RNA-seq reveal extensive reorganization of chromosomes and spatiotemporal reprogramming of the transcriptomic landscape, events responsible for development of the senescence-associated secretory phenotype (SASP). Selectively targeting KDM4 dampens the SASP of senescent stromal cells and enhances the apoptotic index of cancer cells in the treatment-damaged tumor microenvironment (TME), together prolonging overall survival of experimental animals. Our study supports the dynamic change of H3K9/H3K36 methylation marks during cellular senescence, identifies an unusually permissive chromatin state, unmasks KDM4 as a key modulator of the SASP, and presents a novel therapeutic avenue to manipulate cellular senescence and curtail age-related pathologies.

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“…PD-L1 expression is associated with immune checkpoint activation, creating an immunosuppressive tumor microenvironment. Both chemoresistance and immunosuppression decreased in prostate and breast cancer cells after targeting of AREG [ 41 ].…”

Section: Stroma-specific Therapymentioning

confidence: 99%

Chemotherapy resistance and stromal targets in breast cancer treatment: a review

et al. 2020

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Therapy resistance is a known problem in breast cancer and is associated with a variety of mechanisms. The role of the tumor microenvironment in cancer development and resistance mechanisms is becoming increasingly understood. Tumor–stroma is the main component of the tumor microenvironment. Stromal cells like cancer-associated fibroblasts (CAFs) are believed to contribute to chemotherapy resistance via the production of several secreted factors like cytokines and chemokines. CAFs are found to influence disease progression; patients with primary tumors with a high amount of tumor–stroma have a significantly worse outcome. Therefore the role of CAFs resistance mechanisms makes them a promising target in anti-cancer therapy. An overview of recent advances in strategies to target breast cancer stroma is given and the current literature regarding these stromal targets is discussed. CAF-specific proteins as well as secreted molecules involved in tumor–stroma interactions provide possibilities for stroma-specific therapy. The development of stroma-specific therapy is still in its infancy and the available literature is limited. Within the scope of personalized treatment, biomarkers based on the tumor–stroma have future potential for the improvement of treatment via image-guided surgery (IGS) and PET scanning.

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Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD‐L1)‐mediated immunosuppression

Cited by 101 publications

References 55 publications

Variable Expressed Methylation Sites of Aging-related Genes in Asthma

Variable Expressed Methylation Sites of Aging-related Genes in Asthma

KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype

Chemotherapy resistance and stromal targets in breast cancer treatment: a review

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