Estrogen related receptor alpha drives mitochondrial biogenesis and resistance to neoadjuvant chemoradiation in esophageal cancer
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ABSTRACT:
PROVIDER: PRJNA765582 | ENA |
REPOSITORIES: ENA
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Project description:Analysis of peripheral circulating mRNA expression levels in patients undergoing neoadjuvant chemoradiation for esophageal squamous cell carcinoma. The hypothesis test was that chemoradiation alters the circulating mRNA expression profiles and the profiling is predictive of pathological response. Results provide information on the response of circulating mRNAs to chemoradiation and identify novel biomarkers or targets in esophageal squamous cell carcinoma. Total RNA obtained from peripheral whole blood before and after neoadjuvant chemoradiation in patients with esophageal squamous cell carcinoma. 21 patients with 42 samples were analyzed. The expression profiles from pathological complete responders were compared to non-complete responders.
2014-01-01 | E-GEOD-43519 | biostudies-arrayexpress
Project description:Analysis of peripheral circulating mRNA expression levels in patients undergoing neoadjuvant chemoradiation for esophageal squamous cell carcinoma. The hypothesis test was that chemoradiation alters the circulating mRNA expression profiles and the profiling is predictive of pathological response. Results provide information on the response of circulating mRNAs to chemoradiation and identify novel biomarkers or targets in esophageal squamous cell carcinoma.
2014-01-01 | GSE43519 | GEO
Project description:Following exposure to chemoradiation, EAC cells increase their mitochondrial content and associated metabolic processes, which drives treatment resistance. Inhibition of this response using clinically applicable inhibitors of ESRRA in combination with (chemo)radiation shows promising anti-tumor activities and could be further developed for clinical use.
2022-10-17 | GSE184654 | GEO
Project description:Background and Purpose: The current standard of care for locally advanced esophageal and gastroesophageal junctional cancer is neoadjuvant chemoradiation (NCRT) followed by surgery. The genomic and proteomic pathways responsible for response to neoadjuvant chemoradiation are sparsely described, and thus response to treatment cannot be reliably predicted. In this study, we performed an in-depth proteomic analysis of esophageal and gastroesophageal tumors, to describe differences in pathway activation between patients with good and poor prognosis following neoadjuvant chemoradiation. Materials and Methods: This study included locally advanced esophageal and gastroesophageal cancer patients treated with NCRT. The study cohort was dichotomized into two groups of patients- good prognosis (GP) and bad prognosis (BP) according to the post-operative disease-free interval. We performed a mass spectrometry analysis of proteins extracted from the malignant regions of surgical specimens and analyzed data from electronic medical records. Clinical data was correlated with differences in protein expression between GP and BP using validated gene expression pathways. Results: The study included thirty-five patients with adenocarcinoma. GP and BP had statistically significant differences in protein expression patterns. GP exhibited differential enrichment of pathways related to cellular respiration, oxidative phosphorylation and proteins of the RAS oncogene family. Conclusion: In this study we identify enrichment of pathways related to oxidative phosphorylation and RAS oncogene pathway in esophageal cancer patients with a favorable response to NCRT. Larger transcriptomic studies are warranted to portray potential surrogate signature of biomarkers based upon these potential pathways.
2022-05-20 | PXD025192 | Pride
Project description:Neoadjuvant chemoradiotherapy (nCRT) improves outcomes in resectable esophageal adenocarcinoma (EAC), but acquired resistance precludes long-term efficacy. Here, we delineate these resistance mechanisms. RNA sequencing on matched patient samples obtained pre-and post-neoadjuvant treatment reveal that oxidative phosphorylation was the most upregulated of all biological programs following nCRT. Analysis of patient-derived models confirms that mitochondrial content and oxygen consumption strongly increase in response to nCRT and that ionizing radiation is the causative agent. Bioinformatics identifies estrogen-related receptor alpha (ESRRA) as the transcription factor responsible for reprogramming, and overexpression and silencing of ESRRA functionally confirm that its downstream metabolic rewiring contributes to resistance. Pharmacological inhibition of ESRRA successfully sensitizes EAC organoids and patient-derived xenografts to radiation. In conclusion, we report a profound metabolic rewiring following chemoradiation and demonstrate that its inhibition resensitizes EAC cells to radiation. These findings hold broader relevance for other cancer types treated with radiation as well.
| S-EPMC9729822 | biostudies-literature
Project description:Neoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC. We analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LARC cohorts, including a LARC patient RNA sequencing (RNA-seq) dataset from our cohort and GSE15781 and GSE94104 datasets. Gene ontology analysis showed that preoperative CRT significantly enriched the immune response in LARC tissues. Moreover, gene set enrichment analysis revealed six significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways associated with downregulated genes, including mismatch repair (MMR) genes, in LARC tissues after CRT in all three cohorts. Radiation also induced apoptosis and downregulated various MMR system-related genes in three colorectal cancer cells. One patient with LARC showed a change in microsatellite instability (MSI) status after CRT, as demonstrated by the loss of MMR protein and PCR for MSI. Moreover, CRT significantly increased tumor mutational burden in LARC tissues. CIBERSORT analysis revealed that the proportions of M2 macrophages and CD8 T cells were significantly increased after CRT in both the RNA-seq dataset and GSE94104. Notably, preoperative CRT increased various immune biomarker scores, such as the interferon-γ signature, the cytolytic activity and the immune signature. Taken together, our findings demonstrated that neoadjuvant CRT modulated the immune-related characteristics of LARC, suggesting that neoadjuvant CRT may enhance the responsiveness of LARC to immunotherapy.
2023-05-31 | GSE233517 | GEO
Project description:Patients undergoing pancreatic resection at William Beaumont Hospital (Royal Oak, MI) were consented prior to surgery with local IRB oversight. Samples were collected at time of surgery and stored at -80°C according to CAP (College of American Pathologist)-accredited standard operating procedures. Disease pathology of frozen samples was validated with hematoxylin and eosin stained tissue sections from adjacently collected formalin fixed paraffin embedded tissue. The objective of this study was to examine the gene expression patterns of pancreatic adenocarcinoma treated with neoadjuvant chemoradiotherapy compared to pancreatic adenocarcinoma that had not under gone neoadjuvant treatment. The results of this study demonstrate that neoadjuvant therapy alters the gene expression of pancreatic adenocarcinoma
2015-10-01 | GSE60646 | GEO
Project description:Sotigalimab (sotiga) is an agonistic anti-CD40 monoclonal antibody that can modulate anti-tumor immune responses. In a clinical trial of sotiga combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction cancer, treatment induced pathologic complete responses in 38% of patients. Using high-dimensional single cell techniques, we found that sotiga dramatically re-modeled both peripheral immune responses and the tumor microenvironment (TME), increasing components of antigen processing and presentation and altering metabolic pathways in myeloid cells. Concomitant with myeloid cell alterations, sotiga primed new T cell clonotypes, increased T cells with enhanced cytotoxic activity, and decreased the frequency of Tregs in the TME. Clinical responses were associated with both baseline and treatment-induced T cell states. These findings indicate that sotiga induces antigen presentation leading to enhanced T cell activation and clinical response, and that the immune composition of the TME at baseline is important in conferring sensitivity to this treatment approach.
2023-12-11 | GSE244746 | GEO
Project description:Sotigalimab (sotiga) is an agonistic anti-CD40 monoclonal antibody that can modulate anti-tumor immune responses. In a clinical trial of sotiga combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction cancer, treatment induced pathologic complete responses in 38% of patients. Using high-dimensional single cell techniques, we found that sotiga dramatically re-modeled both peripheral immune responses and the tumor microenvironment (TME), increasing components of antigen processing and presentation and altering metabolic pathways in myeloid cells. Concomitant with myeloid cell alterations, sotiga primed new T cell clonotypes, increased T cells with enhanced cytotoxic activity, and decreased the frequency of Tregs in the TME. Clinical responses were associated with both baseline and treatment-induced T cell states. These findings indicate that sotiga induces antigen presentation leading to enhanced T cell activation and clinical response, and that the immune composition of the TME at baseline is important in conferring sensitivity to this treatment approach.
2023-12-11 | GSE244739 | GEO
Project description:Preoperative chemoradiotherapy (CRT) followed by surgery has been proved to improve esophageal squamous cell carcinoma (ESCC) patients’ survival in comparison with surgery alone. However, the outcomes of CRT are heterogeneous, and no clinical or pathological method could predict CRT response. We aim to identify miRNA markers for ESCC CRT-response prediction through miRNA expression analyses. MiRNA expression analyses were performed on pretreatment cancer biopsies from 28 ESCCs who received neoadjuvant CRT and surgery using Agilent human miRNA microarrays based on miRBase (release 18.0) GeneChip®.
2015-07-27 | E-GEOD-59974 | biostudies-arrayexpress