Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis
Marco Biondini,
Camille Lehuédé,
Sébastien Tabariès,
Matthew G. Annis,
Alain Pacis,
Eric H. Ma,
Christine Tam,
Brian E. Hsu,
Yannick Audet-Delage,
Afnan Abu-Thuraia,
Charlotte Girondel,
Valerie Sabourin,
Stephanie P. Totten,
Mariana de Sá Tavares Russo,
Gaëlle Bridon,
Daina Avizonis,
Marie-Christine Guiot,
Julie St-Pierre,
Josie Ursini-Siegel,
Russell Jones,
Peter M. Siegel
Affiliations
Marco Biondini
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Camille Lehuédé
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Sébastien Tabariès
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Matthew G. Annis
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Alain Pacis
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Canadian Center for Computational Genomics, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Eric H. Ma
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
Christine Tam
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Brian E. Hsu
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Yannick Audet-Delage
Department of Biochemistry, Microbiology and Immunology and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada
Afnan Abu-Thuraia
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Charlotte Girondel
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Valerie Sabourin
Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec, Qc, H3A 1A3, Canada
Stephanie P. Totten
Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec, Qc, H3A 1A3, Canada
Mariana de Sá Tavares Russo
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Gaëlle Bridon
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Daina Avizonis
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada
Marie-Christine Guiot
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Pathology, Montreal Neurological Hospital/Institute, McGill University Health Centre, Montréal, Québec, Qc, H3A 1A3, Canada
Julie St-Pierre
Department of Biochemistry, Microbiology and Immunology and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada
Josie Ursini-Siegel
Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec, Qc, H3A 1A3, Canada
Russell Jones
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
Peter M. Siegel
Goodman Cancer Institute, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, Québec, Qc, H3A 1A3, Canada; Corresponding author. Goodman Cancer Institute Department of Medicine McGill University 1160 Pine Avenue, West Cancer Pavilion, Room 513 Montréal, Québec, H3A 1A3, Canada.
Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2′-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations.Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.
