Cell Reports (Sep 2021)
Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging
- Alessia Floerchinger,
- Kendelle J. Murphy,
- Sharissa L. Latham,
- Sean C. Warren,
- Andrew T. McCulloch,
- Young-Kyung Lee,
- Janett Stoehr,
- Pauline Mélénec,
- Cris S. Guaman,
- Xanthe L. Metcalf,
- Victoria Lee,
- Anaiis Zaratzian,
- Andrew Da Silva,
- Michael Tayao,
- Sonia Rolo,
- Monica Phimmachanh,
- Ghazal Sultani,
- Laura McDonald,
- Susan M. Mason,
- Nicola Ferrari,
- Lisa M. Ooms,
- Anna-Karin E. Johnsson,
- Heather J. Spence,
- Michael F. Olson,
- Laura M. Machesky,
- Owen J. Sansom,
- Jennifer P. Morton,
- Christina A. Mitchell,
- Michael S. Samuel,
- David R. Croucher,
- Heidi C.E. Welch,
- Karen Blyth,
- C. Elizabeth Caldon,
- David Herrmann,
- Kurt I. Anderson,
- Paul Timpson,
- Max Nobis
Affiliations
- Alessia Floerchinger
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Kendelle J. Murphy
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Sharissa L. Latham
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Sean C. Warren
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Andrew T. McCulloch
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Young-Kyung Lee
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Janett Stoehr
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Pauline Mélénec
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Cris S. Guaman
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Xanthe L. Metcalf
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Victoria Lee
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Anaiis Zaratzian
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Andrew Da Silva
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Michael Tayao
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Sonia Rolo
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G611BD, UK
- Monica Phimmachanh
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Ghazal Sultani
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Laura McDonald
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G611BD, UK
- Susan M. Mason
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G611BD, UK
- Nicola Ferrari
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G611BD, UK; Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G111QH, UK
- Lisa M. Ooms
- Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, VIC 3800, Australia
- Anna-Karin E. Johnsson
- Signalling Programme, Babraham Institute, Cambridge CB223AT, UK
- Heather J. Spence
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Michael F. Olson
- Department of Chemistry and Biology, Ryerson University, Toronto ON, M5B 2K3, Canada
- Laura M. Machesky
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Owen J. Sansom
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G611BD, UK; Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G111QH, UK
- Jennifer P. Morton
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G611BD, UK; Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G111QH, UK
- Christina A. Mitchell
- Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, VIC 3800, Australia
- Michael S. Samuel
- Centre for Cancer Biology, SA Pathology and University of South Australia; and the School of Medicine, University of Adelaide, Adelaide, SA 5000, Australia
- David R. Croucher
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Heidi C.E. Welch
- Signalling Programme, Babraham Institute, Cambridge CB223AT, UK
- Karen Blyth
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G611BD, UK; Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G111QH, UK
- C. Elizabeth Caldon
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- David Herrmann
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
- Kurt I. Anderson
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G611BD, UK; Francis Crick Institute, London NW11AT, UK
- Paul Timpson
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia; Corresponding author
- Max Nobis
- The Garvan Institute of Medical Research, St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia; Corresponding author
- Journal volume & issue
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Vol. 36,
no. 11
p. 109689
Abstract
Summary: Assessing drug response within live native tissue provides increased fidelity with regards to optimizing efficacy while minimizing off-target effects. Here, using longitudinal intravital imaging of a Rac1-Förster resonance energy transfer (FRET) biosensor mouse coupled with in vivo photoswitching to track intratumoral movement, we help guide treatment scheduling in a live breast cancer setting to impair metastatic progression. We uncover altered Rac1 activity at the center versus invasive border of tumors and demonstrate enhanced Rac1 activity of cells in close proximity to live tumor vasculature using optical window imaging. We further reveal that Rac1 inhibition can enhance tumor cell vulnerability to fluid-flow-induced shear stress and therefore improves overall anti-metastatic response to therapy during transit to secondary sites such as the lung. Collectively, this study demonstrates the utility of single-cell intravital imaging in vivo to demonstrate that Rac1 inhibition can reduce tumor progression and metastases in an autochthonous setting to improve overall survival.
