Real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib

Abstract Oesophageal cancer is the 6th most common cause of cancer related death worldwide. The current standard of care for oesophageal adenocarcinoma (OAC) focuses on neoadjuvant therapy with chemoradiation or chemotherapy, however the 5-year survival rates remain at < 20%. To improve treatment...

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Autores principales:	Amy M. Buckley, Margaret R. Dunne, Maria E. Morrissey, Susan A. Kennedy, Aoife Nolan, Maria Davern, Emma K. Foley, Niamh Clarke, Joanne Lysaght, Narayanasamy Ravi, Dermot O’Toole, Finbar MacCarthy, John V. Reynolds, Breandán N. Kennedy, Jacintha O’Sullivan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e0a0a6fa4475406c8c5b27eb5adbbaa8
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spelling	oai:doaj.org-article:e0a0a6fa4475406c8c5b27eb5adbbaa82021-12-02T16:26:36ZReal-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib10.1038/s41598-020-68777-72045-2322https://doaj.org/article/e0a0a6fa4475406c8c5b27eb5adbbaa82020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-68777-7https://doaj.org/toc/2045-2322Abstract Oesophageal cancer is the 6th most common cause of cancer related death worldwide. The current standard of care for oesophageal adenocarcinoma (OAC) focuses on neoadjuvant therapy with chemoradiation or chemotherapy, however the 5-year survival rates remain at < 20%. To improve treatment outcomes it is critical to further investigate OAC tumour biology, metabolic phenotype and their metabolic adaptation to different oxygen tensions. In this study, by using human ex-vivo explants we demonstrated using real-time metabolic profiling that OAC tumour biopsies have a significantly higher oxygen consumption rate (OCR), a measure of oxidative phosphorylation compared to extracellular acidification rate (ECAR), a measure of glycolysis (p = 0.0004). Previously, we identified a small molecule compound, pyrazinib which enhanced radiosensitivity in OAC. Pyrazinib significantly inhibited OCR in OAC treatment-naïve biopsies (p = 0.0139). Furthermore, OAC biopsies can significantly adapt their metabolic rate in real-time to their environment. Under hypoxic conditions pyrazinib produced a significant reduction in both OCR (p = 0.0313) and ECAR in OAC treatment-naïve biopsies. The inflammatory secretome profile from OAC treatment-naïve biopsies is heterogeneous. OCR was positively correlated with three secreted factors in the tumour conditioned media: vascular endothelial factor A (VEGF-A), IL-1RA and thymic stromal lymphopoietin (TSLP). Pyrazinib significantly inhibited IL-1β secretion (p = 0.0377) and increased IL-3 (p = 0.0020) and IL-17B (p = 0.0181). Importantly, pyrazinib did not directly alter the expression of dendritic cell maturation markers or reduce T-cell viability or activation markers. We present a new method for profiling the metabolic rate of tumour biopsies in real-time and demonstrate the novel anti-metabolic and anti-inflammatory action of pyrazinib ex-vivo in OAC tumours, supporting previous findings in-vitro whereby pyrazinib significantly enhanced radiosensitivity in OAC.Amy M. BuckleyMargaret R. DunneMaria E. MorrisseySusan A. KennedyAoife NolanMaria DavernEmma K. FoleyNiamh ClarkeJoanne LysaghtNarayanasamy RaviDermot O’TooleFinbar MacCarthyJohn V. ReynoldsBreandán N. KennedyJacintha O’SullivanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amy M. Buckley Margaret R. Dunne Maria E. Morrissey Susan A. Kennedy Aoife Nolan Maria Davern Emma K. Foley Niamh Clarke Joanne Lysaght Narayanasamy Ravi Dermot O’Toole Finbar MacCarthy John V. Reynolds Breandán N. Kennedy Jacintha O’Sullivan Real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib
description	Abstract Oesophageal cancer is the 6th most common cause of cancer related death worldwide. The current standard of care for oesophageal adenocarcinoma (OAC) focuses on neoadjuvant therapy with chemoradiation or chemotherapy, however the 5-year survival rates remain at < 20%. To improve treatment outcomes it is critical to further investigate OAC tumour biology, metabolic phenotype and their metabolic adaptation to different oxygen tensions. In this study, by using human ex-vivo explants we demonstrated using real-time metabolic profiling that OAC tumour biopsies have a significantly higher oxygen consumption rate (OCR), a measure of oxidative phosphorylation compared to extracellular acidification rate (ECAR), a measure of glycolysis (p = 0.0004). Previously, we identified a small molecule compound, pyrazinib which enhanced radiosensitivity in OAC. Pyrazinib significantly inhibited OCR in OAC treatment-naïve biopsies (p = 0.0139). Furthermore, OAC biopsies can significantly adapt their metabolic rate in real-time to their environment. Under hypoxic conditions pyrazinib produced a significant reduction in both OCR (p = 0.0313) and ECAR in OAC treatment-naïve biopsies. The inflammatory secretome profile from OAC treatment-naïve biopsies is heterogeneous. OCR was positively correlated with three secreted factors in the tumour conditioned media: vascular endothelial factor A (VEGF-A), IL-1RA and thymic stromal lymphopoietin (TSLP). Pyrazinib significantly inhibited IL-1β secretion (p = 0.0377) and increased IL-3 (p = 0.0020) and IL-17B (p = 0.0181). Importantly, pyrazinib did not directly alter the expression of dendritic cell maturation markers or reduce T-cell viability or activation markers. We present a new method for profiling the metabolic rate of tumour biopsies in real-time and demonstrate the novel anti-metabolic and anti-inflammatory action of pyrazinib ex-vivo in OAC tumours, supporting previous findings in-vitro whereby pyrazinib significantly enhanced radiosensitivity in OAC.
format	article
author	Amy M. Buckley Margaret R. Dunne Maria E. Morrissey Susan A. Kennedy Aoife Nolan Maria Davern Emma K. Foley Niamh Clarke Joanne Lysaght Narayanasamy Ravi Dermot O’Toole Finbar MacCarthy John V. Reynolds Breandán N. Kennedy Jacintha O’Sullivan
author_facet	Amy M. Buckley Margaret R. Dunne Maria E. Morrissey Susan A. Kennedy Aoife Nolan Maria Davern Emma K. Foley Niamh Clarke Joanne Lysaght Narayanasamy Ravi Dermot O’Toole Finbar MacCarthy John V. Reynolds Breandán N. Kennedy Jacintha O’Sullivan
author_sort	Amy M. Buckley
title	Real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib
title_short	Real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib
title_full	Real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib
title_fullStr	Real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib
title_full_unstemmed	Real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib
title_sort	real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with pyrazinib
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/e0a0a6fa4475406c8c5b27eb5adbbaa8
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Real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib

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