Amphiregulin and Epiregulin confer radioresistance in esophageal squamous cell carcinoma through oxidative phosphorylation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE293873 | GEO | 2026/02/11
REPOSITORIES: GEO
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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.
2024-12-04 | GSE274064 | GEO
Project description:Background: The gonadotropin-induced resumption of oocyte meiosis in preovulatory follicles is preceded by expression of epidermal growth factor (EGF)-like peptides, amphiregulin (AREG) and epiregulin (EREG), in mural granulosa and cumulus cells. Both the gonadotropins and the EGF-like peptides possess the capacity to stimulate resumption of oocyte meiosis in vitro via activation of a broad signaling network in cumulus cells. To better understand the rapid genomic actions of gonadotropins (FSH) and EGF-like peptides, we analyzed transcriptomes of cumulus cells at 3 h after their stimulation. Methods: We hybridized aRNA from cumulus cells to a pig oligonucleotide microarray and compared the transcriptomes of FSH- and AREG/EREG-stimulated cumulus cells with untreated control cells and vice versa. The identified over- and underexpressed genes were subjected to functional genomic analysis according to their molecular and cellular functions. The expression pattern of 50 selected genes with a known or potential function in ovarian development was verified by real-time qRT-PCR. Results: Both FSH and AREG/EREG increased the expression of genes associated with regulation of cell proliferation, cell migration, blood coagulation and extracellular matrix remodeling. FSH alone induced the expression of genes involved in inflammatory response and in the response to reactive oxygen species. Moreover, FSH stimulated the expression of genes closely related to some ovulatory events either exclusively or significantly more than AREG/EREG (AREG, ADAMTS1, HAS2, TNFAIP6, PLAUR, PLAT, and HSD17B7). In contrast to AREG/EREG, FSH also increased the expression of genes coding for key transcription factors (CEBPB, FOS, ID1/3, and NR5A2), which may contribute to the differing expression profiles of FSH- and AREG/EREG-treated cumulus cells. Conclusions: The impact of FSH on cumulus cell gene transcription was higher than the impact of EGF-like factors in terms of the number of cell functions affected as well as the number of over- and underexpressed genes. Both FSH and EGF-like factors overexpressed genes involved in the post-ovulatory switch in steroidogenesis and tissue remodelling. However, FSH was remarkably more efficient in the up-regulation of several specific genes essential for ovulation of matured oocytes and also genes that been reported to play an important role in maturation of cumulus-enclosed oocytes in vitro.
2015-09-30 | GSE64858 | GEO
Project description:Our lab has identified a completely unexpected requirement for ERBB signalling in KRAS‐driven Lung Adenocarcinoma (LuAd). We have shown that this requirement is present from the very outset of lung tumour initiation, and, crucially, we have found a pronounced increase in ERBB signalling during progression from low grade adenocarcinoma to locally invasive disease. We hypothesize that this increased activity, which manifests as strongly elevated expression of multiple EGF/ERBB-family ligands, such as Amphiregulin (AREG), and paracrine activation of ERBB2 on infiltrating macrophages, may be exploited for early detection of KRAS‐ driven malignancy. Alongside a more general increase in AREG expression as tumours progress to higher grade disease, we find individual cells that express extremely high levels of AREG mRNA. We refer to these cells as AREG super-expressers and their lineage identity is unknown. Cell morphology suggests they maybe epithelial, however, unlike the bulk of tumours, these cells fail to express the lung epithelial marker SPC and staining for cytokeratins is inconclusive. Their detection at and adjacent to the tumour:normal interface suggests that they maybe disseminating tumour cells undergoing EMT. Alternatively, they may belong to another lung-resident or infiltrating population, induced to express AREG through direct contact with tumour cells. Immediately adjacent to progressing tumours we find large numbers of F4/80-positive macrophages that stain strongly for tyrosine phosphorylated ERBB2 (p-Tyr-ERBB2), suggesting paracrine activation in response to local production of ERBB ligands. The aim of this part of the work is to identify the cell lineage of the AREG superexpressers and to investigate the effect of ERBB-inhibition using the multi-ERBB inhibitor Neratinib.
2025-09-15 | GSE307621 | GEO
Project description:To characterize potential biomarkers and underlying mechanisms that prompt pathological complete response (pCR) rate of neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) patients.LARC patients from two hospitals were enrolled with pre-nCRT biopsy tissues examined by pressure cycling technology (PCT) combined with data-independent acquisition (DIA) mass spectrometry. Tumor regression grade (TRG) evaluation was performed with the surgical tissues after nCRT to estimate the efficacy of nCRT. Proteins up regulated in pCR patients were highlighted and immune infiltration analysis was carried out. The candidate biomarker FOSL2 (FOS Like 2, AP-1 Transcription Factor Subunit), was selected and verified its role in vitro and vivo. We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 different cells with or without chemoradiotherapy.
2025-09-09 | GSE213009 | GEO
Project description:AREG/EREG and outcomes from anti-EGFR therapy in mCRC
| PRJEB63103 | ENA
Project description:The role of brain immune compartments in glioma evolution remains elusive. We profiled immune cells in glioma microenvironment and the matched peripheral blood from 11 patients at a single-cell level. Notably, glioblastoma exhibits specific infiltration of certain blood-originated monocytes expressing EGFR ligands including EREG and AREG, coined as tumor-associated monocytes (TAMo). TAMo infiltration is mutually exclusive with EGFR alterations (P = 0.019), while co-occurring with mesenchymal subtype (P = 4.7x10-7) and marking worse prognosis (P = 0.004 and 0.032 in two independent cohorts). Evolutionary analysis of initial-recurrent glioma pairs and single-cell study of a multi-centric glioblastoma reveals remarkable association between elevated TAMo and glioma mesenchymal transformation. Further analysis identifies FOSL2 as a master regulator of TAMo. The roles of FOSL2-EREG/AREG-EGFR signaling axis in promoting glioma invasion were verified experimentally. Collectively, we have identified TAMo in tumor microenvironment and revealed its driving role in activating EGFR signaling to shape glioma evolution.
2023-08-01 | GSE237779 | GEO
Project description:Introduction: Neoadjuvant chemoradiotherapy (nCRT) was the foundation treatment for locally advanced rectal cancer (LARC). The nCRT can improve the efficacy of immunotherapy on account of its in-situ vaccine effect. Objective: The aim is to identify stable and reliable transcriptome signatures to predict the efficacy of immune checkpoint blockade (ICB) in patients with LARC. Methods: Immunophenotyping was established by using xCell immune cell infiltration abundance and consistent clustering in GSE39582 and verified in several data sets. The effects of immunophenotyping, follicular regulatory T cells, tumor associated fibroblasts (CAF) and tertiary lymphoid structures (TLS) signatures on the efficacy of ICB were analyzed by using IMvigor210, GSE91061 and an independent Daping Hospital (DPH) cohort. Results: There are four stable and repeatable immune subtypes in rectal cancer, among which C1 is low immune infiltration type, C2 is high interstitial infiltration type, C3 is high immune infiltration type and C4 is ion channel type. C2 is mainly characterized by high infiltration CAF, C3 is characterized by high infiltration of cytotoxic T lymphocytes, high expression of PD-L1 and TLS. In rectal cancer patients receiving nCRT, immunophenotyping was not significantly associated with pathological remission rate, but immunophenotyping was an independent prognostic factor of RFS. In IMvigor210 patients treatment with atezolizumab, the pathological remission rates of C1, C2, C3 and C4 were 23.86%, 10.94%, 33.33% and 23.08% respectively (χ2 = 8.981, P = 0.029), which were 11.76%, 50.00%, 42.86% and 0.0% respectively in the GSE91061 patients treatment with nivolumab (Fisher's exact probability, P = 0.018). Both follicular regulatory T cells and CAF showed a further impact on the ICB therapeutic efficacy of C2 and C3 subtype. In addition, both GSE91404 and DPH cohorts showed that nCRT treatment induced a significant increase in the expression of TNFRSF9 and abundance of macrophages in C3 subtype. Conclusion: Our data suggest that there are four immune types of rectal cancer, which are related to the prognosis of patients. Among them, C3 and some C2 subtypes represents the patients who may benefit from ICB after nCRT treatment.
2022-09-17 | GSE213331 | GEO
Project description:Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Nearly 50% of the patients who receive the most intensive treatment develop leukemia relapse. AML cells are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS) for survival, especially refractory leukemia, but how OXPHOS contributes to the leukemia progression is unclear and noncytotoxic strategy to inhibit OXPHOS is lacking. Here, we demonstrate for the first time that ZDHHC21 palmitoyltransferase serves as a key regulator to regulate the OXPHOS hyperactivity in AML cells. The depletion of ZDHHC21 effectively inhibited OXPHOS activity and induced the myeloid differentiation of AML cell lines and patient-derived AML specimens. Mechanistically, ZDHHC21 specifically catalyzes the palmitoylation of mitochondrial kinase AK2 and further activates OXPHOS to arrest myeloid differentiation. Moreover, inhibition of ZDHHC21 eradicated the AML blasts and prolonged the survival of NOD/SCID mice inoculated with AML cell lines and PDX-AML cells. Besides, targeting ZDHHC21 to suppress OXPHOS markedly enhances the chemotherapy efficacy in refractory leukemia. Together, these findings not only uncover the new biological function of palmitoyltransferase ZDHHC21 in regulating AML oxidative phosphorylation, but also indicate ZDHHC21 inhibition as a potential therapy for patients with AML especially refractory leukemia.
2024-11-30 | GSE218229 | GEO
Project description:Recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) is a severe, frequently lethal condition. Targeted therapy includes epidermal growth factor receptor (EGFR) blockade, but overall response rates are low and predictive biomarkers amiss. Deepened understanding of molecular networks governing EGFR-driven progression are required to explore predictive markers and therapeutic targets. We have mapped EGFR-mediated local invasion in a 3D-model using photoconvertible cell-tracers and uncovered invasion-associated, differentially expressed genes (DEGs) correlated with EGFR/MAPK activity and epithelial-to-mesenchymal transition (EMT) in primary malignant cells. A gene regulatory network (GRN) of local invasion was defined, composed of the central hubs inhibin subunit beta alpha (INHBA) and SLUG, and druggable effectors integrin subunit beta 4 (ITGβ4), its ligand laminin 5 (LAMB3/LAMC2), sphingosine kinase 1 (SPHK1), and EGFR ligand amphiregulin (AREG). Blockade of INHBA repressed local invasion, which was rescued by Activin A, Laminin 5, and sphingosine-1-phosphate, proving functional interconnection of the GRN. Functional DEGs (fDEGs) and, most prominently, central hub IHNBA, were associated with tumor buds in TCGA-HNSCC. Newly defined EGFR-activity subtypes, primarily dictated by AREG and epiregulin (EREG), show enhanced fDEGs expression, EMT correlation, and prognostic value. Cell-communication revealed strong interactions of AREG/EREG-governed EGFR-activities with non-malignant cells, potentially impacting on tumor progression. High expression of fDEGs enriched in EGFR-activities (INHBA, ITGA3, ITGΒ4, LAMA3, LAMC2, MT2A, EREG) was associated with response to Cetuximab in PDX models and R/M-HNSCC patients. Thus, we describe a novel GRN of EGFR-mediated local invasion and define druggable effectors with predictive potential regarding the response to Cetuximab.
2025-03-26 | GSE273463 | GEO
Project description:Interventions: Single arm study to explore the efficacy of cetuximab in combination with Irinotecan based treatment in advanced stage RAS/BRAF wild type right sided colorectal cancer with high AREG/EREG expression.
Dosing regimens include either of the following standard of care regimens for the administration of cetuximab in combination with Irinotecan. They will be chosen at physician discretion;
1) Cetuximab 500mg/m2 Intravenous infusion Day 1 of a 14 day cycle in combination with Irinotecan Intravenous infusion 180mg/m2 Day 1 of a 14 day cycle until disease progression, unacceptable toxicity or withdrawal of consent.
2)Cetuximab 500mg/m2 Intravenous infusion Day 1 of a 14 day cycle in combination with Irinotecan Intravenous infusion 180mg/m2 Day 1 of a 14 day cycle AND Calcium folinate 50mg Intravenous bolus Day 1, Fluorouracil 400mg/m2 Intravenous infusion on Day 1 followed by continuous intravenous infusion Fluorouracil 2400mg/m2 pump over 46 hours until disease progression, unacceptable toxicity or withdrawal of patient consent.
Archival tumour tissue from advanced colorectal cancer patients will be tested using an immunohistochemistry assay for Amphiregulin/epiregulin (AREG/EREG)to determine a population of patients who may benefit from this combination of therapy.
Participants will be asked to consent to pre- screening of their archival samples for the purpose of AREG/EREG testing. Once consented, testing of archival tissue may take place at any point during the participants first line treatment. There is no time limit for testing results and being considered eligible for the main study. Once AREG/EREG testing results have been received by the site Investigator ,if clinically appropriate the main study participant information and consent form (PICF) will be o
Primary outcome(s): To determine progression free survival (PFS) of patients with right-sided, RAS/BRAF wild-type advanced Colorectal Cancer (CRC ) with high AREG/EREG expression (AREG/EREG high) following treatment with cetuximab + irinotecan based treatment in the second or later line setting. Progression Free Survival will be assessed by CT Chest/Abdomen/Pelvis (or MRI for participants unable to receive contrast) at 8 week intervals during the treatment phase, and at End of Treatment or until disease progression.[Disease status will be assessed at the following time points; CT scan with IV contrast (or MRI for participants unable to receive contrast) every 8 weeks during treatment phase, until disease progression or cessation of treatment for other reasons : ie: patient choice, unacceptable toxicity. Disease status will be accessed within 4 weeks of the last dose of treatment. After a patient has progressed on study treatment, no further study specific follow-up assessments will be required. All patients will be followed until death or study completion, to collect details of any further treatment and survival status.]
Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Other;Type of endpoint: Efficacy
| 93851 | ecrin-mdr-crc