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Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging.

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posted on 24.09.2021, 10:26 by 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 CE Welch, Karen Blyth, C Elizabeth Caldon, David Herrmann, Kurt I Anderson, Paul Timpson, Max Nobis
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.

Funding

Crick (Grant ID: 10010, Grant title: STP Light Microscopy)

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