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Radiation-induced amphiregulin drives tumor metastasis

ABSTRACT: The anti-tumor effect of radiotherapy (RT) beyond the treatment field - the abscopal effect - has garnered much interest. By contrast, the potentially harmful impact of radiation in promoting metastasis is less well studied. Here, we show that RT induces the expression of epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) in tumor cells, which reprograms EGFR+ myeloid cells toward an immunosuppressive phenotype and reduces phagocytosis. This stimulates distant metastasis growth in both patients and pre-clinical murine tumor models. The inhibition of these tumor-promoting factors induced by RT may represent a novel therapeutic strategy to improve patient outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE291151 | GEO | 2025/03/05

REPOSITORIES: GEO

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Radiation-induced amphiregulin drives tumor metastases

Project description:In this study, we demonstrate that radiation induces the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) in tumor cells, which stimulates distant metastasis proliferation in both patients and pre-clinical murine tumor models. Using single-cell RNAseq (sc-RNAseq), we characterized the effects of AREG-induction on immune cells in the lung metastatic microenvironment of B6 mice.

2025-02-27 | GSE250375 | GEO

Amphiregulin mediates non-cell-autonomous effect of senescence on reprogramming

Project description:Cellular senescence is an irreversible growth arrest with a highly dynamic secretome, termed the senescence-associated secretory phenotype (SASP). Senescence has been implicated in somatic reprogramming to pluripotency. The cell-intrinsic proliferation arrest is a barrier for reprogramming, whereas the SASP facilitates the cell fate conversion in nonsenescent cells. However, the mechanisms by which reprogramming-induced senescence regulates cell plasticity are not well understood. Here, we have further investigated how the heterogeneity of paracrine senescence impacts reprogramming. We show that senescence promotes in vitro reprogramming in a stress-dependent manner. We identified a catalog of SASP factors and pathways potentially involved in the cell fate conversion using an unbiased proteomic analysis. Amphiregulin (AREG), a growth factor frequently secreted by the senescent cells, promotes in vitro reprogramming by accelerating proliferation and MET via the EGFR signaling pathway. Of note, AREG treatment diminished the negative effect of donor age on reprogramming. Finally, AREG enhances in vivo reprogramming in the skeletal muscle. Hence, senescence could facilitate cellular plasticity via various SASP factors to promote reprogramming and tissue repair.

2022-07-28 | PXD028590 | Pride

Amphiregulin Upregulated in Esophageal Squamous Cell Carcinoma Cells upon Direct Contact with Cancer-Associated Fibroblasts

Project description:Cancer-associated fibroblasts (CAFs) are a pivotal component of the tumor microenvironment, significantly contributing to the progression of esophageal squamous cell carcinoma (ESCC). Direct co-culture of human bone marrow-derived mesenchymal stem cells (MSCs), one of the origins of CAFs, with ESCC cell line, led to increased amphiregulin (AREG) expression and secretion in the ESCC cells. Consequently, the expression and phosphorylation of the AREG receptor EGFR were upregulated in co-cultured ESCC cells. Moreover, AREG treatment enhanced ESCC cell survival and migration through the EGFR-Erk/p38 signaling pathway. Immunohistochemical analysis of AREG using human ESCC tissues showed a positive correlation between the intensity of AREG expression in tumor invasive front and the expression level of the CAF marker FAP. Furthermore, bioinformatics database analysis confirmed a significant upregulation of AREG expression in ESCC tissues compared to normal tissues. These findings suggest that AREG is involved in CAF-mediated ESCC progression and could be a novel therapeutic target for ESCC.

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Radiation-induced amphiregulin drives tumor metastasis

Project description:Radiation-induced amphiregulin drives tumor metastasis

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The EGF Receptor Ligand Amphiregulin Controls Cell Division via FoxM1

Project description:We analyzed the effect of tetracycline (Tet)-inducible amphiregulin (AREG) silencing on the transcriptome of immortalized human N/TERT keratinocytes in the presence or absence of exogenous rhEGF. Tetracycline-mediated AREG silencing significantly altered the expression of 2,331 genes, 623 of which were not normalized towards normal by treatment with EGF. Genes irreversibly up-regulated by suppression of AREG overlapped with genes involved in keratinocyte differentiation. A significant proportion of the irreversibly down-regulated genes featured upstream binding sites recognized by FoxM1

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Effect of Amphiregulin on global gene expression in injured skeletal muscle in the presence or absence of CD4+Foxp3+ regulatory T cells (Tregs).

Project description:Global gene expression analysis of injured skeletal muscle showed that amphiregulin (Areg), a growth factor over-expressed by muscle Treg cells, enhances muscle regeneration both in the presence and in the absence of Tregs. Foxp3-DTR+ and Foxp3-DTR- mice were injured with cardiotoxin in TA muscle at day 0 and treated with diphtheria toxin every other day from day 0 until dissection. Amphiregulin or PBS were administered im on day 0 and ip every other day until dissection. TA muscle was flash-frozen and RNA was extracted using Trizol. RNA from whole tissue samples was amplified, labeled, and hybridized to Affymetrix Mouse Gene 1.0 ST Arrays.

2013-12-15 | E-GEOD-50097 | biostudies-arrayexpress

EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

Project description:Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be found. Here we identified that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in Th cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that AREG-EGFR signaling induces HIF1α, which binds and transactivates IL-9, IRF4 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppress their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.

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Effect of Amphiregulin on global gene expression in injured skeletal muscle in the presence or absence of CD4+Foxp3+ regulatory T cells (Tregs).

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HDAC3 maintains oocyte meiosis arrest by repressing amphiregulin expression before the LH surge [HDAC3cKO]

Project description:It is known that granulosa cells (GCs) mediate gonadotropin-induced oocyte meiosis resumption by releasing EGF-like factors in mammal, however, the detail molecular mechanisms remain unclear. Here, we demonstrate that luteinizing hormone (LH) surge induced histone deacetylase 3 (HDAC3) downregulation in GCs is essential for oocyte maturation. Before the LH surge, HDAC3 is highly expressed in GCs. Transcription factors, such as FOXO1, mediates recruitment of HDAC3 to the amphiregulin (Areg) promoter, which suppresses AREG expression. With the LH surge, decreased HDAC3 in GCs enables histone H3K14 acetylation and binding of the SP1 transcription factor to the Areg promoter to initiate AREG transcription and oocyte maturation. Conditional knockout of Hdac3 in granulosa cells in vivo or inhibition of HDAC3 activity in vitro promotes the maturation of oocytes independent of LH. Taking together, HDAC3 in GCs within ovarian follicles acts as a negative regulator of EGF-like growth factor expression before the LH surge.

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HDAC3 maintains oocyte meiosis arrest by repressing amphiregulin expression before the LH surge [mGC-HDACi]

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