Rosalind and Morris
Goodman Cancer
Institute Principal
Investigators
- Transcriptional control of intracellular metabolism by members of the superfamily of nuclear hormone receptors in normal and cancer cells.
- Non-canonical activity of nuclear mTOR on gene expression.
- Development of the poor outcome neuroendocrine prostate cancer subtype in response to androgen deprivation therapy.
Dr. Giguère's research interests primarily focus on the identification of gene programs under the control of nuclear receptors and the molecular mechanisms underlying the cell specific activity of these receptors in response to physiological and pathological stresses. Our main research area is centered on investigating the role of the orphan estrogen related receptors (ERRα, β and γ) in sustaining energy production and mitochondrial biogenesis at the cellular level, supporting the development and function of individual organs, and maintaining the metabolic homeostasis of the whole organism via metabolite-dependent inter-organ communications. Elucidating the roles played by the three ERRs in promoting the metabolic adaptation of cancer cells in response to changes in their microenvironment and therapeutic insults is also a topic intense investigation by our team.
The serine/threonine kinase mTOR is known to play essential roles in the control of cell growth and proliferation. By phosphorylating specific substrates in the cytoplasm, mTOR influences mRNA translation into proteins and the metabolic state of the cell. However, our team has recently uncovered that mTOR also plays a crucial role in the nucleus as a transcription factor. Our goal is to decipher the mechanisms by which mTOR is induced to translocate to the nucleus and interact with the chromatin, identify its transcriptional partners at specific genomic loci, and identify the oncogenic programs under the control of nuclear mTOR in cancer cells.
Our team also investigates the relationship between metabolic disorders and the development of the cancer phenotype. We explore the progression of fatty liver diseases to hepatocellular carcinoma, more specifically the integration of abnormal nuclear receptors and mTOR transcriptional activities in promoting the evolution of metabolic diseases toward cancer.
What we are
currently
working on
Dysregulation of energy metabolism is associated with a wide range of metabolic diseases and considered a hallmark of cancer. Transcriptional regulation of gene expression is one of the fundamental molecular mechanisms by which cells can control energy homeostasis. Hence, modulation of the activity of transcription factors implicated in metabolic control has emerged as an important target for therapeutic intervention. Nuclear receptors, ligand activated transcription factors and critical regulators of energy homeostasis, are thus ideal targets for therapeutic interventions. Indeed, our past work has revealed that the ERRs can act as converging hubs to receive and propagate a large variety of metabolic signals leading to the transcriptional control of energy metabolism in both normal and cancer cells. Gain or loss of nuclear receptor functions can thus considerably impact tumour progression and emergence of drug resistance. In a similar manner, hyperactivation of both canonical and non-canonical mTOR signaling pathways influences oncogenic gene programs.
Our aims are twofold: 1) identify gene programs under the direct transcriptional control of nuclear receptors and mTOR and the underlying molecular mechanisms dictating their activity on chromatin; 2) develop pre-clinical models to study nuclear receptor and mTOR activities in metabolic diseases and cancer, including genetically engineered mouse models (GEMM) and cell lines, xenografts as well as organoids and subject them to comprehensive functional and omic studies to identify actionable pathways suitable for therapeutic interventions.
- Récepteurs nucléaires et interaction avec mTOR lorsque lié à la chromatine Dans ce travail, la spectrométrie de masse par immunoprécipitation rapide des protéines endogènes (RIME), une technique qui combine ChIP avec la spectrométrie de masse (MS), est utilisée pour caractériser spécifiquement les interactomes des récepteurs nucléaires et de mTOR lorsque liés à la chromatine dans les tissus métaboliques et cellules cancéreuses de diverses origines. La validation de ces interactions sur la fonction cellulaire est ensuite réalisée à l'aide d'un profilage intégré de phosphoprotéomique, transcriptomique et métabolomique. Les signatures omiques intégrées de ces analyses peuvent ensuite être sondées pour mettre en évidence de nouvelles avenues thérapeutiques potentielles pout contrer les maladies métaboliques et le cancer. Nuclear receptor and mTOR chromatin-bound interactomes In this work, Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (RIME), a technique that combines ChIP with mass spectrometry (MS), is used to specifically characterize the chromatin-bound nuclear receptor and mTOR interactomes in metabolic tissues and cancer cells of various origins. Validation of these interactions on cell function is then accomplished using integrated phosphoproteomic, transcriptomic and metabolic profiling. Integrated omics signatures derived from these analyses can then be probed to highlight potential new therapeutic avenues for metabolic diseases and cancer.
- Récepteurs nucléaires sensibles aux nutriments contrôlant l'homéostasie énergétique systémique La stéatose hépatique non alcoolique (NAFLD – Nonalcoholic fatty liver disease), principalement définie comme une accumulation excessive de lipides dans le foie, est la manifestation hépatique de troubles métaboliques associés à l'augmentation globale du taux d'obésité et de diabète de type 2. La stéatohépatite non alcoolique (NASH –nonalcoholic steatohepatitis) est une forme plus grave de NAFLD qui se caractérise en outre par une inflammation chronique et une fibrose. Les lésions hépatiques associées à la NASH peuvent entraîner une cirrhose, la nécessité d'une greffe du foie et l'initiation et la progression du carcinome hépatocellulaire (CHC). Les médicaments pharmaceutiques pour le traitement de la NAFLD ou de la NASH n'ont pas encore été approuvés. L'objectif de ce projet est d'étudier comment un sous-ensemble de récepteurs nucléaires agissent de concert pour réguler le métabolisme énergétique hépatique et comment la perturbation de leur activité transcriptionnelle peut rompre l'équilibre de l'homéostasie hépatique et entraîner la progression de la NAFLD/NASH vers le CHC. Control of systemic energy homeostasis by nutrient-sensing nuclear receptors Nonalcoholic fatty liver disease (NAFLD), primarily defined as excessive lipid accumulation in the liver, is the hepatic manifestation of metabolic disorders associated with the global increased rate of obesity and type 2 diabetes. Nonalcoholic steatohepatitis (NASH) is a more severe form of NAFLD that is further characterized by chronic inflammation and fibrosis. Liver injuries associated with NASH can lead to cirrhosis, the need for a liver transplant and to the initiation and progression of hepatocellular carcinoma (HCC). Pharmaceutical medicines for the treatment of NAFLD or NASH have yet to be approved. The goal of this project is to investigate how a subset of nuclear receptors act in concert to regulate hepatic energy metabolism and how perturbation of their transcriptional activity may break the balance of liver homeostasis and drive NAFL/NASH progression toward HCC.
- Rôle de l'ERRα dans la progression du cancer du sein et la résistance aux médicaments Notre équipe a précédemment démontré que la réexpression de l'ERRα endogène via la signalisation mTOR dans les cellules cancéreuses du sein HER2 positives confère une résistance au lapatinib, un inhibiteur de la kinase HER2. L'expression d'ERRα conduit à l'activation d'un programme métabolique permettant la survie cellulaire malgré l'inhibition constante de la signalisation HER2. L'inhibition pharmacologique de l'ERRα empêche cette adaptation métabolique et restaure la sensibilité au lapatinib dans les cellules résistantes, démontrant le potentiel d'inhibition de l'ERRα comme traitement adjuvant efficace dans le cancer du sein HER2+. L'identification récente des mutations ESSRA communes au cancer du sein triple négatif (TNBC) et à d'autres cancers offre désormais l'opportunité unique de sonder les mécanismes moléculaires sous-jacents au rôle joué par ERRα dans la progression du cancer et d'étudier le potentiel de nouvelles options thérapeutiques pour les cancers à faible taux de survie. Les objectifs de ce projet sont 1) générer des modèles cellulaires modifiés pour exprimer les mutations du point chaud ESRRA et de soumettre ces cellules à un profilage phénotypique et multi-omique complet pour identifier des vulnérabilités exploitables dans les voies intracellulaires métaboliques qui favorisent la croissance tumorale; 2) étudier l'impact de ces mutations sur l'interaction des protéines associées à ERRα sur la chromatine et découvrir de nouveaux interacteurs de ERRα spécifiques au TNBC et à la mutation présente dans ces tumeurs. Role of ERRα in breast cancer progression and drug resistance Our team has previously shown that re-expression of endogenous ERRα through mTOR signaling in HER2 positive breast cancer cells confers resistance to lapatinib, a HER2 kinase inhibitor. ERRα expression leads activation of a metabolic program enabling cell survival despite constant inhibition of HER2 signaling. Pharmacological inhibition of ERRα prevents this metabolic adaptation and restores lapatinib sensitivity in resistant cells, demonstrating the potential for ERRα inhibition as an effective adjuvant therapy in HER2+ breast cancer. The recent identification of ESSRA mutations common to triple negative breast cancer (TNBC) and other cancers now offers the unique opportunity to probe the molecular mechanisms underlying the role played by ERRα in cancer progression and investigate the potential for new therapeutic options for poor outcome cancers. The goals of this project are 1) to generate cell models modified to express ESRRA hotspot mutations and subject these cells to a comprehensive phenotypic and multi-omics profiling to identify actionable vulnerabilities in metabolic and growth promoting intracellular pathways; 2) to investigate the impact of mutations on the interaction of ERRα-associated proteins on chromatin and discover novel TNBC- and mutation-specific ERRα interactors.
- Fellow of the Royal Society of Canada (2009)
- Served as the Director of the Molecular Oncology Group (1994-2006) and Joint Head of the Cancer Axis at MUHC (2000-2006)
- Served on the Advisory Committee on Research (ACOR) of the National Cancer Institute of Canada (NCIC) (2000-2006)
Our team
Anthony Alfonso Étudiant à la maîtrise MSc Student 
Catherine-Rosa Dufour Technicien.ne de recherche Research Technician 
Charlotte Scholtes Candidat.e postdoctoral.e Postdoctoral Fellow 
Emma Pleynet Étudiant.e de premier cycle Undergraduate Student 
Lingwei (Stephanie) Han Étudiant.e au doctorat PhD Student 
Megan Katz Étudiant.e à la maîtrise MSc Student 
Phillipe Hutton Étudiant.e à la maîtrise MSc Student 
Samaneh Kamyabiazar 
Majid Ghahremani Technicien.ne de recherche Research Technician 
Younes Medkour Candidat.e postdoctoral.e Postdoctoral Fellow
Major discoveries
- 1997 Placental abnormalities in mouse embryos lacking orphan nuclear hormone receptor ERRα.
- 1999 Ligand-independent recruitment of SRC-1 by estrogen receptor β through phosphorylation of activation function.
- 2005 From the cover: Location analysis of estrogen receptor α target promoters reveal that FOXA1 defines a domain of the estrogen response.
- 2007 Genome-wide orchestration of cardiac functions by orphan nuclear receptors ERRα and γ.
- 2010 miR-378* mediates metabolic shift in breast cancer cells via the PGC-1β/ERRγ transcriptional pathway.
- 2013 Molecular and genetic crosstalks between mTOR and ERRα are key determinants of rapamycin-induced non-alcoholic fatty liver.
- 2017 Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer.
- 2022 Insulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis.
- 2022 Transcriptional regulation of energy metabolism by nuclear receptors.
Research Partners
Get in touch
3655 Promenade Sir William Osler
Montreal, Quebec H3G 1Y6
Office: 710
Lab: 711
T. 514 398-5899
T. 514 398-5787
F. 514-398-8578
vincent.giguere@mcgill.ca
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