1. Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging
- Author
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Laura M. Machesky, Sharissa L. Latham, Karen Blyth, Owen J. Sansom, Paul Timpson, Cris S. Guaman, Victoria Lee, Nicola Ferrari, Anaiis Zaratzian, Sean C. Warren, Susan M. Mason, Pauline Mélénec, Lisa M Ooms, C. Elizabeth Caldon, Andrew M. Da Silva, Andrew T. McCulloch, Michael F. Olson, Xanthe L. Metcalf, Ghazal Sultani, Monica Phimmachanh, David Herrmann, Michael Tayao, Max Nobis, Alessia Floerchinger, Janett Stoehr, Jennifer P. Morton, Anna-Karin E. Johnsson, Christina Anne Mitchell, Heather J. Spence, Kendelle J. Murphy, David R. Croucher, Sonia Rolo, Heidi C.E. Welch, Young-Kyung Lee, Michael S. Samuel, Laura McDonald, Kurt I. Anderson, Floerchinger, Alessia, Murphy, Kendelle J, Latham, Sharissa L, Warren, Sean C, Samuel, Michael S, and Nobis, Max
- Subjects
rac1 GTP-Binding Protein ,FLIM ,Lung Neoplasms ,Cell Survival ,QH301-705.5 ,drug response ,RAC1 ,Breast Neoplasms ,Biosensing Techniques ,FRET biosensors ,Tumor vasculature ,small GTPases ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,Imaging ,Mice ,Breast cancer ,Cell Movement ,Cell Line, Tumor ,Fluorescence Resonance Energy Transfer ,Medicine ,Animals ,Humans ,metastasis ,Biology (General) ,Metastatic cascade ,Mice, Inbred BALB C ,RAc1 activity ,business.industry ,imaging ,Intravital Imaging ,medicine.disease ,Förster resonance energy transfer ,Pyrimidines ,Tumor progression ,Cancer research ,Aminoquinolines ,Female ,intravital imaging ,single-cell intravital imaging ,business ,Shear Strength ,Rac1 ,Signal Transduction - Abstract
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-Forster 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.
- Published
- 2021
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