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3. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial

Author

Mukherjee, Somnath, Morgan, Carys, Parsons, Simon L, Bhuva, Neel, Campbell, Sorcha, Grogan, Liam, Leonard, Greg, Bateman, Andrew R, Mitchell, Catherine, O'Reilly, Seamus, Mulroe, Eibhlin, McLoughlin, Olivia, Shevlin, Anna, Shannon, Aoife M, Marron, Jacinta, Nolan, Marc, Burch, Grace, Costello, Michelle, Griffiths, Daniel, Cozens, Kelly, Foley, Emma, Donohoe, Claire L, O'Farrell, Catherine, Moore, Jennifer, O'Sullivan, Jacintha, Reynolds, John V, Preston, Shaun R, O'Neill, Brian, Lowery, Maeve A, Baeksgaard, Lene, Crosby, Thomas, Cunningham, Moya, Cuffe, Sinead, Griffiths, Gareth O, Parker, Imelda, Risumlund, Signe Lenora, Roy, Rajarshi, Falk, Stephen, Hanna, George B, Bartlett, Frederick R, Alvarez-Iglesias, Alberto, Achiam, Michael P, Nilsson, Magnus, Piessen, Guillaume, Ravi, Narayanasamy, O'Toole, Dermot, Johnston, Ciaran, McDermott, Raymond S, Turkington, Richard C, Wahed, Shajahan, Sothi, Sharmila, Ford, Hugo, Wadley, Martin S, and Power, Derek

Published
2023
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4. KH-Type Splicing Regulatory Protein Controls Colorectal Cancer Cell Growth and Modulates the Tumor Microenvironment

Author

Caiazza, Francesco, Oficjalska, Katarzyna, Tosetto, Miriam, Phelan, James J, Noonan, Sinéad, Martin, Petra, Killick, Kate, Breen, Laura, O'Neill, Fiona, Nolan, Blathnaid, Furney, Simon, Power, Robert, Fennelly, David, Craik, Charles S, O'Sullivan, Jacintha, Sheahan, Kieran, Doherty, Glen A, and Ryan, Elizabeth J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Colo-Rectal Cancer, Cancer, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Aged, 80 and over, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Colorectal Neoplasms, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Prognosis, RNA-Binding Proteins, Survival Rate, Trans-Activators, Tumor Cells, Cultured, Tumor Microenvironment, Xenograft Model Antitumor Assays, Medical and Health Sciences, Pathology, Biomedical and clinical sciences, Health sciences
Abstract

KH-type splicing regulatory protein (KHSRP) is a multifunctional nucleic acid binding protein implicated in key aspects of cancer cell biology: inflammation and cell-fate determination. However, the role KHSRP plays in colorectal cancer (CRC) tumorigenesis remains largely unknown. Using a combination of in silico analysis of large data sets, ex vivo analysis of protein expression in patients, and mechanistic studies using in vitro models of CRC, we investigated the oncogenic role of KHSRP. We demonstrated KHSRP expression in the epithelial and stromal compartments of both primary and metastatic tumors. Elevated expression was found in tumor versus matched normal tissue, and these findings were validated in larger independent cohorts in silico. KHSRP expression was a prognostic indicator of worse overall survival (hazard ratio, 3.74; 95% CI, 1.43-22.97; P = 0.0138). Mechanistic data in CRC cell line models supported a role of KHSRP in driving epithelial cell proliferation in both a primary and metastatic setting, through control of the G1/S transition. In addition, KHSRP promoted a proangiogenic extracellular environment by regulating the secretion of oncogenic proteins involved in diverse cellular processes, such as migration and response to cellular stress. Our study provides novel mechanistic insight into the tumor-promoting effects of KHSRP in CRC.

Published
2019

5. Assessing Circulating Tumour DNA (ctDNA) as a Biomarker for Anal Cancer Management: A Systematic Review

Author

Temperley, Hugo C., primary, Fannon, Timothy, additional, O’Sullivan, Niall J., additional, O’Neill, Maeve, additional, Mac Curtain, Benjamin M., additional, Gilham, Charles, additional, O’Sullivan, Jacintha, additional, O’Kane, Grainne, additional, Mehigan, Brian J., additional, O’Toole, Sharon, additional, Larkin, John O., additional, Gallagher, David, additional, McCormick, Paul, additional, and Kelly, Michael E., additional

Published
2024
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6. Evolutionary double-bind treatment using radiotherapy and NK cell-based immunotherapy in prostate cancer

Author

Luddy, Kimberly A, primary, West, Jeffrey, additional, Robertson-Tessi, Mark, additional, Desai, Bina, additional, Bursell, Taylor M., additional, Barrett, Sarah, additional, O’Sullivan, Jacintha, additional, Marignol, Laure, additional, Gatenby, Robert A, additional, Brown, Joel S, additional, Anderson, Alexander RA, additional, and O’Farrelly, Cliona, additional

Published
2024
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7. Human Macrophages Activate Bystander Neutrophils’ Metabolism and Effector Functions When Challenged with Mycobacterium tuberculosis

Author

Murphy, Dearbhla M., primary, Walsh, Anastasija, additional, Stein, Laura, additional, Petrasca, Andreea, additional, Cox, Donal J., additional, Brown, Kevin, additional, Duffin, Emily, additional, Jameson, Gráinne, additional, Connolly, Sarah A., additional, O’Connell, Fiona, additional, O’Sullivan, Jacintha, additional, Basdeo, Sharee A., additional, Keane, Joseph, additional, and Phelan, James J., additional

Published
2024
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10. Assessing circulating tumour DNA (ctDNA) as a prognostic biomarker in locally advanced rectal cancer: a systematic review and meta-analysis.

Author

O'Sullivan, Niall J., Temperley, Hugo C., Kyle, Eimear T., Sweeney, Kevin J., O'Neill, Maeve, Gilham, Charles, O'Sullivan, Jacintha, O'Kane, Grainne, Mehigan, Brian, O'Toole, Sharon, Larkin, John, Gallagher, David, McCormick, Paul, and Kelly, Michael E.

Subjects
RECTAL cancer, CIRCULATING tumor DNA, BIOMARKERS, POSTOPERATIVE period, DISEASE relapse
Abstract

Introduction: Circulating tumour DNA (ctDNA) has emerged as a promising biomarker in various cancer types, including locally advanced rectal cancer (LARC), offering potential insights into disease progression, treatment response and recurrence. This review aims to comprehensively evaluate the utility of ctDNA as a prognostic biomarker in LARC. Methods: PubMed, EMBASE and Web of Science were searched as part of our review. Studies investigating the utility of ctDNA in locally advanced rectal cancer (LARC) were assessed for eligibility. Quality assessment of included studies was performed using the Newcastle Ottawa Scale (NOS) risk of bias tool. Outcomes extracted included basic participant characteristics, ctDNA details and survival data. A meta-analysis was performed on eligible studies to determine pooled recurrence-free survival (RFS). Results: Twenty-two studies involving 1676 participants were included in our analysis. Methodological quality categorised by the Newcastle Ottawa Scale was generally satisfactory across included studies. ctDNA detected at various time intervals was generally associated with poor outcomes across included studies. Meta-analysis demonstrated a pooled hazard ratio of 8.87 (95% CI 4.91–16.03) and 15.15 (95% CI 8.21–27.95), indicating an increased risk of recurrence with ctDNA positivity in the post-neoadjuvant and post-operative periods respectively. Conclusion: Our systematic review provides evidence supporting the prognostic utility of ctDNA in patients with LARC, particularly in identifying patients at higher risk of disease recurrence in the post-neoadjuvant and post-operative periods. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Protein kinase C beta II suppresses colorectal cancer by regulating IGF-1 mediated cell survival

Author

Dowling, Catríona M, Phelan, James, Callender, Julia A, Cathcart, Mary Clare, Mehigan, Brian, McCormick, Paul, Dalton, Tara, Coffey, John C, Newton, Alexandra C, O’Sullivan, Jacintha, and Kiely, Patrick A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Colo-Rectal Cancer, Clinical Research, Cancer, Genetics, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Aged, 80 and over, Apoptosis, Biomarkers, Tumor, Cell Movement, Cell Proliferation, Colorectal Neoplasms, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Insulin-Like Growth Factor I, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Invasiveness, Prognosis, Protein Kinase C beta, Survival Rate, Tissue Array Analysis, Tumor Cells, Cultured, protein kinase C, IGF-1, cell survival, tumour suppressor, colorectal cancer, Oncology and carcinogenesis
Abstract

Despite extensive efforts, cancer therapies directed at the Protein Kinase C (PKC) family of serine/threonine kinases have failed in clinical trials. These therapies have been directed at inhibiting PKC and have, in some cases, worsened disease outcome. Here we examine colon cancer patients and show not only that PKC Beta II is a tumour suppressor, but patients with low levels of this isozyme have significantly decreased disease free survival. Specifically, analysis of gene expression levels of all PKC genes in matched normal and cancer tissue samples from colon cancer patients revealed a striking down-regulation of the gene coding PKC Beta in the cancer tissue (n = 21). Tissue microarray analysis revealed a dramatic down-regulation of PKC Beta II protein levels in both the epithelial and stromal diseased tissue (n = 166). Of clinical significance, low levels of the protein in the normal tissue of patients is associated with a low (10%) 10 year survival compared with a much higher (60%) survival in patients with relatively high levels of the protein. Consistent with PKC Beta II levels protecting against colon cancer, overexpression of PKC Beta II in colon cancer cell lines reveals that PKC Beta II reverses transformation in cell based assays. Further to this, activation of PKC Beta II results in a dramatic downregulation of IGF-I-induced AKT, indicating a role for PKCs in regulating IGF-1 mediated cell survival. Thus, PKC Beta II is a tumour suppressor in colon cancer and low levels serve as a predictor for poor survival outcome.

Published
2016

13. Ergolide mediates anti-cancer effects on metastatic uveal melanoma cells and modulates their cellular and extracellular vesicle proteomes

Author

Sundaramurthi, Husvinee, primary, Tonelotto, Valentina, additional, Wynne, Kieran, additional, O'Connell, Fiona, additional, O’Reilly, Eve, additional, Costa-Garcia, Marcel, additional, Kovácsházi, Csenger, additional, Kittel, Agnes, additional, Marcone, Simone, additional, Blanco, Alfonso, additional, Pallinger, Eva, additional, Hambalkó, Szabolcs, additional, Piulats Rodriguez, Jose Maria, additional, Ferdinandy, Péter, additional, O'Sullivan, Jacintha, additional, Matallanas, David, additional, Jensen, Lasse D., additional, Giricz, Zoltán, additional, and Kennedy, Breandán N., additional

Published
2023
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14. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial

Author

Reynolds, John V, primary, Preston, Shaun R, additional, O'Neill, Brian, additional, Lowery, Maeve A, additional, Baeksgaard, Lene, additional, Crosby, Thomas, additional, Cunningham, Moya, additional, Cuffe, Sinead, additional, Griffiths, Gareth O, additional, Parker, Imelda, additional, Risumlund, Signe Lenora, additional, Roy, Rajarshi, additional, Falk, Stephen, additional, Hanna, George B, additional, Bartlett, Frederick R, additional, Alvarez-Iglesias, Alberto, additional, Achiam, Michael P, additional, Nilsson, Magnus, additional, Piessen, Guillaume, additional, Ravi, Narayanasamy, additional, O'Toole, Dermot, additional, Johnston, Ciaran, additional, McDermott, Raymond S, additional, Turkington, Richard C, additional, Wahed, Shajahan, additional, Sothi, Sharmila, additional, Ford, Hugo, additional, Wadley, Martin S, additional, Power, Derek, additional, Mukherjee, Somnath, additional, Morgan, Carys, additional, Parsons, Simon L, additional, Bhuva, Neel, additional, Campbell, Sorcha, additional, Grogan, Liam, additional, Leonard, Greg, additional, Bateman, Andrew R, additional, Mitchell, Catherine, additional, O'Reilly, Seamus, additional, Mulroe, Eibhlin, additional, McLoughlin, Olivia, additional, Shevlin, Anna, additional, Shannon, Aoife M, additional, Marron, Jacinta, additional, Nolan, Marc, additional, Burch, Grace, additional, Costello, Michelle, additional, Griffiths, Daniel, additional, Cozens, Kelly, additional, Foley, Emma, additional, Donohoe, Claire L, additional, O'Farrell, Catherine, additional, Moore, Jennifer, additional, and O'Sullivan, Jacintha, additional

Published
2023
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15. Characterizing caspase-1 involvement during esophageal disease progression

Author

Barber, Gillian, Anand, Akanksha, Katarzyna Oficjalska, Phelan, James J., Heeran, Aisling B., Flis, Ewelina, Clarke, Niamh E., Watson, Jenny A., Strangmann, Julia, Flood, Brian, O’Neill, Hazel, O’Toole, Dermot, MacCarthy, Finbar, Ravi, Narayanasamy, Reynolds, John V., Kay, Elaine W., Quante, Michael, O’Sullivan, Jacintha, and Creagh, Emma M.

Published
2020
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18. Metformin is a metabolic modulator and radiosensitiser in rectal cancer

Author

Buckley, Croí E., primary, O’Brien, Rebecca M., additional, Nugent, Timothy S., additional, Donlon, Noel E., additional, O’Connell, Fiona, additional, Reynolds, John V., additional, Hafeez, Adnan, additional, O’Ríordáin, Diarmuid S., additional, Hannon, Robert A., additional, Neary, Paul, additional, Kalbassi, Reza, additional, Mehigan, Brian J., additional, McCormick, Paul H., additional, Dunne, Cara, additional, Kelly, Michael E., additional, Larkin, John O., additional, O’Sullivan, Jacintha, additional, and Lynam-Lennon, Niamh, additional

Published
2023
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26. Energy Metabolism, Metabolite, and Inflammatory Profiles in Human Ex Vivo Adipose Tissue Are Influenced by Obesity Status, Metabolic Dysfunction, and Treatment Regimes in Patients with Oesophageal Adenocarcinoma

Author

O’Connell, Fiona, primary, Mylod, Eimear, additional, Donlon, Noel E., additional, Heeran, Aisling B., additional, Butler, Christine, additional, Bhardwaj, Anshul, additional, Ramjit, Sinead, additional, Durand, Michael, additional, Lambe, Gerard, additional, Tansey, Paul, additional, Welartne, Ivan, additional, Sheahan, Kevin P., additional, Yin, Xiaofei, additional, Donohoe, Claire L., additional, Ravi, Narayanasamy, additional, Dunne, Margaret R., additional, Brennan, Lorraine, additional, Reynolds, John V., additional, Roche, Helen M., additional, and O’Sullivan, Jacintha, additional

Published
2023
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29. 1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model

Author

Slater, Kayleigh, primary, Bosch, Rosa, additional, Smith, Kaelin Francis, additional, Jahangir, Chowdhury Arif, additional, Garcia-Mulero, Sandra, additional, Rahman, Arman, additional, O’Connell, Fiona, additional, Piulats, Josep M., additional, O’Neill, Valerie, additional, Horgan, Noel, additional, Coupland, Sarah E., additional, O’Sullivan, Jacintha, additional, Gallagher, William M., additional, Villanueva, Alberto, additional, and Kennedy, Breandán N., additional

Published
2023
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34. Identification of plasma proteins associated with oesophageal cancer chemotherapeutic treatment outcomes using SWATH-MS

Author

Guo, Naici, primary, Minas, Giorgos, additional, Synowsky, Silvia A., additional, Dunne, Margaret R., additional, Ahmed, Hasnain, additional, McShane, Rhiannon, additional, Bhardwaj, Anshul, additional, Donlon, Noel E., additional, Lorton, Cliona, additional, O'Sullivan, Jacintha, additional, Reynolds, John V., additional, Caie, Peter D., additional, Shirran, Sally L., additional, Lynch, Andy G., additional, Stewart, Alan J., additional, and Arya, Swati, additional

Published
2022
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35. Colonic oncostatin M expression evaluated by immunohistochemistry and infliximab therapy outcome in corticosteroid-refractory acute severe ulcerative colitis

Author

O’Connell, Jim, primary, Doherty, Jayne, additional, Buckley, Amy, additional, Cormican, David, additional, Dunne, Cara, additional, Hartery, Karen, additional, Larkin, John, additional, MacCarthy, Finbar, additional, McCormick, Paul, additional, McKiernan, Susan, additional, Mehigan, Brian, additional, Muldoon, Cian, additional, Ryan, Ciara, additional, O’Sullivan, Jacintha, additional, and Kevans, David, additional

Published
2022
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37. Energy Metabolism Is Altered in Radioresistant Rectal Cancer.

Author

Buckley, Croí E., Yin, Xiaofei, Meltzer, Sebastian, Ree, Anne Hansen, Redalen, Kathrine Røe, Brennan, Lorraine, O'Sullivan, Jacintha, and Lynam-Lennon, Niamh

Subjects
RECTAL cancer, ENERGY metabolism, GLYCOLYSIS, NEOADJUVANT chemotherapy, FUNCTIONAL analysis, METABOLOMICS, DOSE-response relationship (Radiation)
Abstract

Resistance to neoadjuvant chemoradiation therapy is a significant clinical challenge in the management of rectal cancer. There is an unmet need to identify the underlying mechanisms of treatment resistance to enable the development of biomarkers predictive of response and novel treatment strategies to improve therapeutic response. In this study, an in vitro model of inherently radioresistant rectal cancer was identified and characterized to identify mechanisms underlying radioresistance in rectal cancer. Transcriptomic and functional analysis demonstrated significant alterations in multiple molecular pathways, including the cell cycle, DNA repair efficiency and upregulation of oxidative phosphorylation-related genes in radioresistant SW837 rectal cancer cells. Real-time metabolic profiling demonstrated decreased reliance on glycolysis and enhanced mitochondrial spare respiratory capacity in radioresistant SW837 cells when compared to radiosensitive HCT116 cells. Metabolomic profiling of pre-treatment serum samples from rectal cancer patients (n = 52) identified 16 metabolites significantly associated with subsequent pathological response to neoadjuvant chemoradiation therapy. Thirteen of these metabolites were also significantly associated with overall survival. This study demonstrates, for the first time, a role for metabolic reprograming in the radioresistance of rectal cancer in vitro and highlights a potential role for altered metabolites as novel circulating predictive markers of treatment response in rectal cancer patients. [ABSTRACT FROM AUTHOR]

Published
2023
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39. The Associations of Selenoprotein Genetic Variants with the Risks of Colorectal Adenoma and Colorectal Cancer: Case–Control Studies in Irish and Czech Populations

Author

Mukhtar, Maryam, primary, Ashfield, Niall, additional, Vodickova, Ludmila, additional, Vymetalkova, Veronika, additional, Levy, Miroslav, additional, Liska, Václav, additional, Bruha, Jan, additional, Bendova, Petra, additional, O’Sullivan, Jacintha, additional, Doherty, Glen, additional, Sheahan, Kieran, additional, Nolan, Blathnaid, additional, Vodicka, Pavel, additional, and Hughes, David J., additional

Published
2022
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40. Abstract 1990: Exploring the immune-metabolic mechanisms of adipose tissue in oesophageal adenocarcinoma

Author

O'Connell, Fiona, primary, Mylod, Eimear, additional, Heeran, Ailsing B., additional, Donlon, Noel E., additional, Davern, Maria, additional, Butler, Christine, additional, Bhardwaj, Anshul, additional, Donohoe, Claire, additional, Ravi, Narayanasamy, additional, Renyolds, John V., additional, Dunne, Margaret R., additional, Roche, Helen M., additional, and O'Sullivan, Jacintha, additional

Published
2022
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41. Impact of radiotherapy on the immune landscape in oesophageal adenocarcinoma

Author

Donlon, Noel E, primary, Davern, Maria, additional, O’Connell, Fiona, additional, Sheppard, Andrew, additional, Heeran, Aisling, additional, Bhardwaj, Anshul, additional, Butler, Christine, additional, Narayanasamy, Ravi, additional, Donohoe, Claire, additional, Phelan, James J, additional, Lynam-Lennon, Niamh, additional, Dunne, Margaret R, additional, Maher, Stephen, additional, O’Sullivan, Jacintha, additional, Reynolds, John V, additional, and Lysaght, Joanne, additional

Published
2022
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42. Telehealth Delivery of a Multi-Disciplinary Rehabilitation Programme for Upper Gastro-Intestinal Cancer: ReStOre@Home Feasibility Study

Author

Brennan, Louise, primary, Sadeghi, Fatemeh, additional, O’Neill, Linda, additional, Guinan, Emer, additional, Smyth, Laura, additional, Sheill, Grainne, additional, Smyth, Emily, additional, Doyle, Suzanne L., additional, Timon, Claire M., additional, Connolly, Deirdre, additional, O’Sullivan, Jacintha, additional, Reynolds, John V., additional, and Hussey, Juliette, additional

Published
2022
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43. Differential Effects of Dietary versus Exercise Intervention on Intrahepatic MAIT Cells and Histological Features of NAFLD

Author

Naimimohasses, Sara, primary, O’Gorman, Philip, additional, Wright, Ciara, additional, Ni Fhloinn, Deirdre, additional, Holden, Dean, additional, Conlon, Niall, additional, Monaghan, Ann, additional, Kennedy, Megan, additional, Gormley, John, additional, Beddy, Peter, additional, Finn, Stephen Patrick, additional, Lysaght, Joanne, additional, O’Sullivan, Jacintha, additional, Dunne, Margaret R., additional, Norris, Suzanne, additional, and Moore, J. Bernadette, additional

Published
2022
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44. AB065. SOH22ABS054. Oesophageal cancer surgery promotes a pro-tumour, pro-metastatic phenotype that is partly inhibited by immunotherapy

Author

Donlon, Noel, primary, Davern, Maria, additional, Sheppard, Andrew, additional, O’Connell, Fiona, additional, Moran, Brendan, additional, Nugent, Tim, additional, Conroy, Melissa, additional, Dunne, Margaret, additional, O’Sullivan, Jacintha, additional, Ravi, Narayanasamy, additional, Donohoe, Claire, additional, Reynolds, John, additional, and Lysaght, Joanne, additional

Published
2022
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45. AB064. SOH22ABS053. Strategies to boost immune function in oesophageal adenocarcinoma—hypofractionated radiotherapy may be superior to current CROSS regimen chemo-radiation

Author

Donlon, Noel, primary, Davern, Maria, additional, Sheppard, Andrew, additional, O’Connell, Fiona, additional, Nugent, Tim, additional, Ravi, Narayanasamy, additional, Donohoe, Claire, additional, Conroy, Melissa, additional, Dunne, Margaret, additional, Maher, Stephen, additional, O’Sullivan, Jacintha, additional, Reynolds, John, additional, and Lysaght, Joanne, additional

Published
2022
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46. Energy Metabolism, Metabolite, and Inflammatory Profiles in Human Ex Vivo Adipose Tissue Are Influenced by Obesity Status, Metabolic Dysfunction, and Treatment Regimes in Patients with Oesophageal Adenocarcinoma.

Author

O'Connell, Fiona, Mylod, Eimear, Donlon, Noel E., Heeran, Aisling B., Butler, Christine, Bhardwaj, Anshul, Ramjit, Sinead, Durand, Michael, Lambe, Gerard, Tansey, Paul, Welartne, Ivan, Sheahan, Kevin P., Yin, Xiaofei, Donohoe, Claire L., Ravi, Narayanasamy, Dunne, Margaret R., Brennan, Lorraine, Reynolds, John V., Roche, Helen M., and O'Sullivan, Jacintha

Subjects
ENERGY metabolism, ADENOCARCINOMA, OBESITY, CYTOKINES, INTERLEUKINS, INFLAMMATION, LIQUID chromatography, CANCER patients, COMPARATIVE studies, CHEMORADIOTHERAPY, RESEARCH funding, ENZYME-linked immunosorbent assay, MASS spectrometry, CHEMOKINES, METABOLITES, ADIPOSE tissues, ESOPHAGEAL tumors
Abstract

Simple Summary: Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and is strongly linked to obesity status and metabolic dysfunction. This study for the first time has conducted a detailed assessment of adipose tissue metabolism, as well as assessing adipose secreted pro-inflammatory, metabolite, and lipid profiles to determine whether these profiles correlate with significant clinical parameters in OAC patients including obesity, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Overall, in this study, increases in metabolic profiles linked with oxidative phosphorylation, pro-inflammatory cytokines, and metabolites associated with aiding tumorigenesis have been identified in the most viscerally obese OAC patients and in patients with metabolic dysfunction. These results raise the question of whether targeting these altered signalling mechanisms could aid current treatment strategies. Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and has a strong link to obesity. To better elucidate the role of visceral adiposity in this disease state, a full metabolic profile combined with analysis of secreted pro-inflammatory cytokines, metabolites, and lipid profiles were assessed in human ex vivo adipose tissue explants from obese and non-obese OAC patients. These data were then related to extensive clinical data including obesity status, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Real-time energy metabolism profiles were assessed using the seahorse technology. Adipose explant conditioned media was screened using multiplex ELISA to assess secreted levels of 54 pro-inflammatory mediators. Targeted secreted metabolite and lipid profiles were analysed using Ultra-High-Performance Liquid Chromatography coupled with Mass Spectrometry. Adipose tissue explants and matched clinical data were collected from OAC patients (n = 32). Compared to visceral fat from non-obese patients (n = 16), visceral fat explants from obese OAC patients (n = 16) had significantly elevated oxidative phosphorylation metabolism profiles and an increase in Eotaxin-3, IL-17A, IL-17D, IL-3, MCP-1, and MDC and altered secretions of glutamine associated metabolites. Adipose explants from patients with metabolic dysfunction correlated with increased oxidative phosphorylation metabolism, and increases in IL-5, IL-7, SAA, VEGF-C, triacylglycerides, and metabolites compared with metabolically healthy patients. Adipose explants generated from patients who had previously received neo-adjuvant chemotherapy (n = 14) showed elevated secretions of pro-inflammatory mediators, IL-12p40, IL-1α, IL-22, and TNF-β and a decreased expression of triacylglycerides. Furthermore, decreased secreted levels of triacylglycerides were also observed in the adipose secretome of patients who received the chemotherapy-only regimen FLOT compared with patients who received no neo-adjuvant treatment or chemo-radiotherapy regimen CROSS. For those patients who showed the poorest response to currently available treatments, their adipose tissue was associated with higher glycolytic metabolism compared to patients who had good treatment responses. This study demonstrates that the adipose secretome in OAC patients is enriched with mediators that could prime the tumour microenvironment to aid tumour progression and attenuate responses to conventional cancer treatments, an effect which appears to be augmented by obesity and metabolic dysfunction and exposure to different treatment regimes. [ABSTRACT FROM AUTHOR]

Published
2023
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48. The Impact of Esophageal Oncological Surgery on Perioperative Immune Function; Implications for Adjuvant Immune Checkpoint Inhibition

Author

Donlon, Noel E., primary, Davern, Maria, additional, Sheppard, Andrew D., additional, O’Connell, Fiona, additional, Dunne, Margaret R., additional, Hayes, Conall, additional, Mylod, Eimear, additional, Ramjit, Sinead, additional, Temperley, Hugo, additional, Mac Lean, Michael, additional, Cotter, Gillian, additional, Bhardwaj, Anshul, additional, Butler, Christine, additional, Conroy, Melissa J., additional, O’Sullivan, Jacintha, additional, Ravi, Narayanasamy, additional, Donohoe, Claire L., additional, Reynolds, John V., additional, and Lysaght, Joanne, additional

Published
2022
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