Rosalind and Morris
Goodman Cancer
Institute Principal
Investigators
Professor Peter Siegel’s laboratory focuses on:
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Investigating the mediators of general and organ-specific metastasis
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Adaptation and modulation of metastatic microenvironment by cancer.
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Identifying how metabolic adaptation/plasticity promotes metastatic fitness.
Elucidating functionally important and clinically relevant mechanisms that drive metastatic progression.
The most devastating aspect of a cancer diagnosis is the emergence of metastatic disease, which signifies that cancer cells have spread from the primary tumour to distant sites in the body. Once cancer has spread, the disease is largely incurable. Research pursued in Dr. Peter Siegel’s laboratory focuses on defining the molecular and cellular processes that facilitate cancer metastasis. These include tumour cell intrinsic processes such a cancer cell migration and invasion. Our research also investigates how cancer cells influence and respond to distinct microenvironments in the primary tumour as well as distant metastatic sites. Thus, our research program is dedicated towards the identification of clinically relevant, functional mediators of cancer metastasis. It is anticipated that these candidates will represent attractive targets for the development of therapeutic agents for improved management of metastatic cancers.
What we are
currently
working on
Metastatic tumour cells must overcome numerous barriers that prevent their dissemination to distant organs and tissues. Traditionally, these steps have been broken down to include local invasion through the basement membrane, migration and intravasation into the lymphatic or hematogenous systems, survival during transit in the circulation, evasion of host anti-tumour immunity, adhesion/extravasation at the target site and reestablishment of a growing tumour mass in a foreign microenvironment. Communication between the tumour and its microenvironment is likely to be the single most important determinant for organ-specific metastasis. Thus, both tumour intrinsic and microenvironmental factors play important roles in controlling the metastatic behavior of cancer cells.
Our goal is to take the information we gain from our research to identify candidate targets against which novel therapeutic agents can be devised in the hope to improve the clinical management of metastatic cancer. We have several ongoing projects in which therapeutic agents are being generated and tested against targets that have emerged from our studies.
- Adaptations et modulations du microenvironnement métastatique par le cancer. La capacité des cellules cancéreuses à former des tumeurs et des métastases dépend en grande partie de leur interaction avec les cellules résidentes dans les tissus et les cellules infiltrantes du système immunitaire. Les cellules cancéreuses doivent développer des mécanismes pour établir un microenvironnement immunosuppresseur, ce qui leur permet d’échapper à la surveillance et à l’élimination par le système immunitaire. En effet, l’immunothérapie est conçue pour altérer la capacité des cellules cancéreuses à supprimer l’immunité anti-tumorale.
Nos recherches ont identifié un rôle du système immunitaire incluant les neutrophiles et/ou les cellules NK dans la mise en place d’un microenvironnement immunosuppresseur dans les métastases hépatiques. Grâce à des analyses protéomique et d’expression génique, nous étudions les mécanismes de l’immunosuppression médiée par les neutrophiles dans les métastases hépatiques.
Nous avons également identifié un rôle clé pour la glycoprotéine GPNMB dans l’établissement d’un microenvironnement immunosuppresseur dans le cancer du sein. Grâce à la cytométrie de masse par imagerie, nous étudions les mécanismes par lesquels GPNMB module le microenvironnement immunitaire des tumeurs primaires et des lésions métastatiques.
Adaptation and modulation of metastatic microenvironment by cancer. The ability of cancer cells to form tumours and metastasize largely depends on their interaction with tissue-resident and infiltrating cells of the immune system. Cancer cells must develop mechanisms to establish an immunosuppressive microenvironment, which allows them to escape immune surveillance and destruction. Indeed, immunotherapy is designed to impair the ability of cancer cells to suppress anti-tumour immunity.
Our research has identified a role for the immune system including neutrophils and/or NK cells in the establishment of an immunosuppressive microenvironment in liver metastasis. Through proteomic and gene expression analysis we are investigating the mechanisms of neutrophil mediated immunosuppression in liver metastasis.
We have also identified a key role for the glycoprotein GPNMB in establishing an immunosuppressive microenvironment in breast cancer. Through imaging mass cytometry, we are investigating the mechanisms through which GPNMB modulates the immune microenvironment primary tumours and metastatic lesions.
- Étude des médiateurs des métastases générales et spécifiques à un organe Nous utilisons des approches d’expression génique, de cytokines et de profilage protéomique pour identifier les médiateurs clés à l’origine des métastases dans des organes/tissus distincts à travers un large éventail de types de cancers solides. Grâce à cette approche, nous avons découvert des protéines de surface cellulaire (GPNMB, Claudin-2), des molécules adaptatrices/échafaudages (ShcA, Lpp, Afadin, Pdlim7), des protéines sécrétées (Chi3l1) et des protéines de liaison à l’ARN (CIRBP). D’un point de vue clinique, le laboratoire valide l’importance de ces médiateurs dans des échantillons dérivés de patients (tumeurs primaires et métastases). Nous étudions le rôle fonctionnel de ces candidats dans la modulation de la croissance tumorale et des métastases à l’aide de modèles de souris transgéniques et de modèles de xénogreffes dérivées de patients.
La migration et l’invasion cellulaires sont deux processus cellulaires fondamentaux qui contribuent à la capacité métastatique des cellules cancéreuses. Les adhésions focales sont des structures cellulaires qui se forment sur la surface ventrale des cellules cancéreuses, et qui relient la matrice extracellulaire au cytosquelette cellulaire. Le contrôle de l’assemblage et du désassemblage de l’adhésion est essentiel au mouvement des cellules cancéreuses. Les invadopodes sont des structures cellulaires distinctes qui se forment sur la surface ventrale des cellules cancéreuses et sont responsables de la dégradation locale des composants de la matrice extracellulaire. Les invadopodes permettent aux cellules cancéreuses d’envahir les tissus. Nous étudions le rôle des signaux biochimiques et biophysiques (rigidité tissulaire/matrice) dans la modulation de la fonction des adhésions cellulaires et des invadopodes ayant un impact sur la capacité métastatique des cellules cancéreuses.
Nos recherches actuelles portent sur les médiateurs des métastases cérébrales, pulmonaires, osseuses et hépatiques dans les cancers solides. Investigating the mediators of general and organ-specific metastasis We are using gene expression, cytokine and proteomic profiling approaches to identify key mediators driving metastasis to distinct organs/tissues in a broad range of solid cancer types. We have uncovered cell surface proteins (GPNMB, Claudin-2), adaptor/scaffold molecules (ShcA, Lpp, Afadin, Pdlim7), secreted proteins (Chi3l1) and RNA binding proteins (CIRBP) using this approach. The laboratory clinically validates the importance of these mediators in patient-derived samples (primary tumours and metastases). We are investigating the functional role of these candidates in modulating tumour growth and metastasis using syngeneic mouse models, transgenic mouse models and patient-derived xenograft models.
Cell migration and invasion are two fundamental cellular processes that contribute to the metastatic ability of cancer cells. Focal adhesions are cellular structures that form on the ventral surface of cancer cells, which links the extracellular matrix to the cell cytoskeleton. Control of adhesion assembly and disassembly is critical for the movement of cancer cells. Invadopodia are distinct cellular structures that form on the ventral surface of cancer cells, which are responsible for the local degradation of extracellular matrix components. Invadopodia allow cancer cells to invade through tissues. We investigate the role that biochemical and biophysical cues (tissue/matrix stiffness) play in modulating the function of cellular adhesions and invadopodia, which impacts the metastatic ability of cancer cells.
Our current research is investigating the mediators of brain, lung, bone and liver metastasis in solid cancers.
- Identifier comment l’adaptation/la plasticité métabolique favorise l’aptitude métastatique. Les cellules cancéreuses doivent continuellement modifier leur métabolisme cellulaire pour faire face à l’évolution des microenvironnements à la fois dans la tumeur primaire et dans les métastases éloignées. Nos travaux ont montré que des stratégies métaboliques spécifiques (métabolisme glycolytique, phosphorylation oxydative) permettent aux cellules cancéreuses de mieux se développer à certains sites (poumon, os), comparé à d’autres (foie). Nous avons également montré que les cellules cancéreuses qui présentent la capacité de basculer entre différentes stratégies métaboliques sont les cellules les plus métastatiques et résistantes aux thérapies. Actuellement, nous examinons comment des microenvironnements tumoraux métastatiques ou primaires distincts influencent le réseau métabolique dans les cellules cancéreuses du foie et du cerveau.
Identifying how metabolic adaptation/plasticity promotes metastatic fitness. Cancer cells must continually alter their cellular metabolism to cope with changing microenvironments in both the primary tumour and distant metastases. Our work has shown that specific metabolic strategies (glycolytic metabolism, oxidative phosphorylation) enable cancer cells to better grow some sites (lung, bone), versus others (liver). We have also shown that cancer cells that exhibit the ability to shift between different metabolic strategies are the cells that are the most metastatic and therapy resistant. Currently, we are examining how distinct metastatic or primary tumour microenvironments influence metabolic wiring in cancer cells in the liver and brain.
- Co-lead of Terry Fox Foundation Program Project Grant in Targeting Metabolic Vulnerabilities in Cancer (07/2019-present)
- Canadian Cancer Society Advisory Council on Research (CCS-ACOR) (04/2016-07/2022)
- Institute of Cancer Research Advisory Board (ICR - IAB) (09/2014-03/2016; 01/2018-03/2020)
- Associate Director of Goodman Cancer Research Centre (07/2013 – 06/2018)
- Interim Director of Goodman Cancer Research Centre (03/2012-06/2013)
- The Simone and Morris Fast Award for Oncology, McGill University (2004-2005)
- Canadian Institutes of Health Research New Investigator Award, McGill University (2004-2009), awarded but declined.
- Harold E. Johns Award, CCS/NCIC Research Scientist Award, McGill University (2004-2010)
- Research Scholar – Junior 2, FRSQ Salary Support Award, McGill University (2010-2012) William Dawson Scholar – Salary and research support, McGill University (2014-present)
- Scientific Distinction Award – Research support award, Quebec Breast Cancer Foundation (2020)
- Gerald Bronfman Department of Oncology Award for Research, McGill University (2020)
Our team
Afnan Abu-Thuraia Candidat.e postdoctoral.e Postdoctoral Fellow 
Alexander Nowakowski Étudiant.e à la maîtrise MSc Student 
Anna-Maria Lazaratos Étudiant.e MDCM-PhD MD/PhD Student 
Yunyun (Anna) Shen Étudiant.e au doctorat PhD Student 
Benjamin Vonniessen Étudiant.e à la maîtrise MSc Student 
Caitlyn Mourcos Étudiant.e à la maîtrise MSc Student 
Charlotte Girondel Candidat.e postdoctoral.e Postdoctoral Fellow 
Emilie Solymoss Étudiant.e à la maîtrise MSc Student 
Marco Biondini Associé.e de recherche Research Associate 
Matthew Annis Associé.e de recherche Research Associate 
Rima Ezzeddine Étudiant.e au doctorat PhD Student 
Sarah Maritan Étudiant.e MDCM-PhD MD/PhD Student 
Sebastien Tabaries Associé.e de recherche Research Associate
Major discoveries
- 2015 PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer.
- 2017 PGC-1α promotes breast cancer metastasis and confers bioenergetic flexibility against metabolic drugs.
- 2017 LPP is a Src substrate required for invadopodia formation and efficient breast cancer lung metastasis.
- 2019 Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer metastasis.
- 2019 Afadin co-operates with Claudin-2 to promote breast cancer metastasis.
- 2021 Invasive growth associated with Cold-Inducible RNA-Binding Protein expression drives recurrence of surgically resected brain metastases.
- 2022 HSP90 inhibitors induce GPNMB cell surface expression and sensitize breast cancer cells to Glembatumumab Vedotin.
- 2023 Highly multiplexed imaging of the brain tumour microenvironment reveals immunological spatial networks that predict survival.
Research Partners
Get in touch
1160 Pine Avenue W.
Montreal, Quebec H3A 1A3
Office: 513
Lab: 508
T. 514-398-4259
T. 514-398-8889
F. 514-398-6769
peter.siegel@mcgill.ca
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