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Metabolism and motility of head and neck cancer: characterisation, prognostication and novel target identification

Metabolism and motility of head and neck cancer: characterisation, prognostication and novel target identification
Metabolism and motility of head and neck cancer: characterisation, prognostication and novel target identification
Head and neck cancer (HNSCC) worldwide affects over 500,000 new people each year and overall mortality has remained at 50% despite promising new treatments. Although FDGPET imaging is in widespread clinical practice, the unique metabolic features of this disease and its subtypes remain poorly understood. We have previously identified Cterminal tensin-like (CTEN; TNS4), a member of the TENSIN gene family that encodes focal adhesion adaptor proteins, as being a likely target geneof a cell’s metabolic sensors (CtBPs). CTEN is also emerging as a prognostic marker in many cancer types but its mechanism of action and clinical relevance in HNSCC was unknown.

Clinical relevance was examined through tissue microarray immuno histochemistry analysis of 260 consecutively treated oropharyngeal cancer patients, demonstrating CTEN expression to have a significant inverse correlation with disease-specific survival, as well as a determinant of chemoradiotherapy resistance. RNA sequencing analysis andin vivo results helped direct in vitro functional assays, utilising gene knockdown methods, resulting in discovery of a novel CTEN function promoting cell survival in HNSCCcell lines, potentially through a TGFβ-dependent pathway.

Linking tumour cell metabolism, we proposed a novel mechanism whereby increasing glycolytic stimuli could regulate CTEN expression via a CtBP2 dependent pathway. We revealed a binding site for the CtBPs on the CTEN promoter viachromatin immuno precipitation analyses. Given the clinical relevance of the human papilloma virus (HPV) in clinical practice,we proceeded to classify the metabolic profiles of both HPV-positive and HPV-negative HNSCC and identified one potential metabolic target, the monocarboxylic acid transporter 1(MCT1). Metabolic profiling confirmed HPV-negative HNSCCas an ideal candidate disease for targeting with a novel MCT1-inhibitor and in vitro treatment resulted in potentially beneficial effects on both metabolic activity and radiosensitivity of cells. We therefore highlighted the potential therapeutic benefits of metabolic agents in novel combination therapy strategies.
University of Southampton
Fleming, Jason
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Fleming, Jason
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Thomas, Gareth
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Blaydes, Jeremy
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Kim, Dae
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Fleming, Jason (2016) Metabolism and motility of head and neck cancer: characterisation, prognostication and novel target identification. University of Southampton, Doctoral Thesis, 248pp.

Record type: Thesis (Doctoral)

Abstract

Head and neck cancer (HNSCC) worldwide affects over 500,000 new people each year and overall mortality has remained at 50% despite promising new treatments. Although FDGPET imaging is in widespread clinical practice, the unique metabolic features of this disease and its subtypes remain poorly understood. We have previously identified Cterminal tensin-like (CTEN; TNS4), a member of the TENSIN gene family that encodes focal adhesion adaptor proteins, as being a likely target geneof a cell’s metabolic sensors (CtBPs). CTEN is also emerging as a prognostic marker in many cancer types but its mechanism of action and clinical relevance in HNSCC was unknown.

Clinical relevance was examined through tissue microarray immuno histochemistry analysis of 260 consecutively treated oropharyngeal cancer patients, demonstrating CTEN expression to have a significant inverse correlation with disease-specific survival, as well as a determinant of chemoradiotherapy resistance. RNA sequencing analysis andin vivo results helped direct in vitro functional assays, utilising gene knockdown methods, resulting in discovery of a novel CTEN function promoting cell survival in HNSCCcell lines, potentially through a TGFβ-dependent pathway.

Linking tumour cell metabolism, we proposed a novel mechanism whereby increasing glycolytic stimuli could regulate CTEN expression via a CtBP2 dependent pathway. We revealed a binding site for the CtBPs on the CTEN promoter viachromatin immuno precipitation analyses. Given the clinical relevance of the human papilloma virus (HPV) in clinical practice,we proceeded to classify the metabolic profiles of both HPV-positive and HPV-negative HNSCC and identified one potential metabolic target, the monocarboxylic acid transporter 1(MCT1). Metabolic profiling confirmed HPV-negative HNSCCas an ideal candidate disease for targeting with a novel MCT1-inhibitor and in vitro treatment resulted in potentially beneficial effects on both metabolic activity and radiosensitivity of cells. We therefore highlighted the potential therapeutic benefits of metabolic agents in novel combination therapy strategies.

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THESIS FLEMING MARCH 2017 - Version of Record
Available under License University of Southampton Thesis Licence.
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Published date: September 2016

Identifiers

Local EPrints ID: 435482
URI: http://eprints.soton.ac.uk/id/eprint/435482
PURE UUID: cfae9b6f-3e12-4397-87ed-24639a189478
ORCID for Jeremy Blaydes: ORCID iD orcid.org/0000-0001-8525-0209

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Date deposited: 07 Nov 2019 17:30
Last modified: 08 Nov 2019 01:37

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Contributors

Author: Jason Fleming
Thesis advisor: Gareth Thomas
Thesis advisor: Jeremy Blaydes ORCID iD
Thesis advisor: Dae Kim

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