Dr. Victor H. Villar
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
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Academic Career Length
17Years (2010-Present)
(Calculated once Scilit publication data is synced: current year − year of first publication + 1)
Representative Publications
View All Publications5 March 2010 in Molecular and Cellular Biochemistry
Journal Article
9 June 2015 in Autophagy
Journal Article
Victor H. VillarFMFaten Merhi
Faten Merhi
MMMojgan Djavahery Mergny
Mojgan Djavahery MergnyRDRaul V. Duran
Raul V. DuranThe remarkable metabolic differences between cancer cells and normal cells result in the potential for targeted cancer therapy. The upregulation of glutaminolysis provides energetic advantages to cancer cells. The recently described link between glutaminolysis and autophagy, mediated by MTORC1, may constitute an attractive target for therapeutic strategies. A combination of therapies targeting simultane-ously cell signaling, cancer metabolism, and autophagy can solve therapy resistance and tumor relapse problems, commonly observed in patients treated with most of the current targeted therapies. In this review we summarize the mechanistic link between glutaminolysis and autophagy, and discuss the impacts of these processes on cancer progression and the potential for therapeutic intervention.
10 August 2021 in Nature Communications
Journal Article
CBClément BODINEAU
Clément BODINEAUMTMercedes Tomé
Mercedes Tomé
SCSarah Courtois
Sarah CourtoisACAna S. H. Costa
Ana S. H. CostaMSMarco Sciacovelli
Marco SciacovelliRDRaul V. Duran
Raul V. Duran +10
Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer.
23 January 2017 in Nature Communications
Journal Article
Victor H. VillarTNTra Ly Nguyen
Tra Ly Nguyen
VDVanessa Delcroix
Vanessa Delcroix
STSilvia Terés
Silvia Terés
MBMarion Bouchecareilh
Marion Bouchecareilh
RDRaul V. Duran
Raul V. Duran +5
A master coordinator of cell growth, mTORC1 is activated by different metabolic inputs, particularly the metabolism of glutamine (glutaminolysis), to control a vast range of cellular processes, including autophagy. As a well-recognized tumour promoter, inhibitors of mTORC1 such as rapamycin have been approved as anti-cancer agents, but their overall outcome in patients is rather poor. Here we show that mTORC1 also presents tumour suppressor features in conditions of nutrient restrictions. Thus, the activation of mTORC1 by glutaminolysis during nutritional imbalance inhibits autophagy and induces apoptosis in cancer cells. Importantly, rapamycin treatment reactivates autophagy and prevents the mTORC1-mediated apoptosis. We also observe that the ability of mTORC1 to activate apoptosis is mediated by the adaptor protein p62. Thus, the mTORC1-mediated upregulation of p62 during nutrient imbalance induces the binding of p62 to caspase 8 and the subsequent activation of the caspase pathway. Our data highlight the role of autophagy as a survival mechanism upon rapamycin treatment.
13 March 2020 in Science Advances
Journal Article
HHHeather Hulme
Heather HulmeLMLynsey M. Meikle
Lynsey M. Meikle
Nicole Strittmatter
Justin Van der HooftJSJohn Swales
John SwalesDWDaniel Wall
Daniel Wall +20
Discovery of novel bacterial metabolites reveals an unprecedented role for the microbiome in gut-brain axis communication.
24 October 2022 in Nature Chemical Biology
Journal Article
Victor H. VillarMAMaria Francesca Allega
Maria Francesca AllegaRDRuhi Deshmukh
Ruhi DeshmukhTATobias Ackermann
Tobias Ackermann
MNMark A. Nakasone
Mark A. NakasoneSTSaverio Tardito
Saverio Tardito +18
Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog,N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels ofN5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis ofN5-methylglutamine over glutamine.N5-methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels ofN5-methylglutamine correlate with tumor burden and GS expression in a β-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite.
About Me
Victor holds a B.S in biochemistry from the University of Chile (Chile). He completed a PhD in cell biology from the University of the Balearic Islands (Spain) in 2013, providing a novel mechanism to explain the synergistic effect between doxorubicin and nilotinib. These combination was evaluated in a clinical trial showing promising results in soft tissue sarcoma patients. Victor did his first postdoctoral training in France, where he described a non-canonical type of apoptotic cell death triggered by the modulation of metabolic pathways and signaling pathways (mTORC1). During his second postdoc at the Beatson Institute, Glasgow, UK, where he received training in methods to study cancer metabolism (LC-MS/MS) using mouse models of hepatocellular carcinoma. During this time, Victor unmasked an alternative product of glutamine synthetase, N5-methylglutamine, which can be a potential biomarker for specific subset of HCC that express high levels of this enzyme.
Victor joined the Mackenzie Institute for early diagnosis in 2023 aiming to identify novel biomarkers for cancer and neurological diseases using untargeted metabolomics (LC-MS/MS) and proteomics.