@article{2c31e62f3dfd4e72a80dcebf4d69cd13,
title = "Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging",
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-F{\"o}rster 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.",
keywords = "breast cancer, FLIM, FRET biosensors, intravital imaging, metastasis, pharmacodynamics, Rac1, small GTPases",
author = "Alessia Floerchinger and Murphy, {Kendelle J.} and Latham, {Sharissa L.} and Warren, {Sean C.} and McCulloch, {Andrew T.} and Lee, {Young Kyung} and Janett Stoehr and Pauline M{\'e}l{\'e}nec and Guaman, {Cris S.} and Metcalf, {Xanthe L.} and Victoria Lee and Anaiis Zaratzian and {Da Silva}, Andrew and Michael Tayao and Sonia Rolo and Monica Phimmachanh and Ghazal Sultani and Laura McDonald and Mason, {Susan M.} and Nicola Ferrari and Ooms, {Lisa M.} and Johnsson, {Anna Karin E.} and Spence, {Heather J.} and Olson, {Michael F.} and Machesky, {Laura M.} and Sansom, {Owen J.} and Morton, {Jennifer P.} and Mitchell, {Christina A.} and Samuel, {Michael S.} and Croucher, {David R.} and Welch, {Heidi C.E.} and Karen Blyth and Caldon, {C. Elizabeth} and David Herrmann and Anderson, {Kurt I.} and Paul Timpson and Max Nobis",
note = "Funding Information: The authors would like to thank the staff at the Australian BioResource, Biological testing facility, tissue culture facility under G. Lehrbach and R. Lyons, the GWCCG Core facility Flow Cytometry under E. Lam and the histology core facility under the leadership of A. Zaratzian at the Garvan Institute of Medical Research. The authors would further like to thank the staff at the Biological Services Unit, Beatson Advanced Imaging Resource and histology facility under the leadership of Colin Nixon at the CRUK Beatson Institute. The FVB/NJ 8th generation clean PyMT-20065 cell line was made available through SEARCHBreast (https://searchbreast.org/). Some images were adapted from Servier Medical Art, licensed under the Creative Commons Attribution 3.0. Unported license (http://creativecommons.org/licenses/by/3.0/). This work was supported by a Cancer Institute New South Wales (CINSW) Early Career fellowship (M.N. and D.H.), an NHMRC Ideas grant (M.N.), NBCF grants (P.T. IIRS-21-077; D.H. IN-17-070 and IIRS-18-129), an NHMRC project grant and Senior Research Fellowship (SRF) (P.T.), St Vincent's Clinical Foundation grants (M.N. D.H. P.T. and C.E.C.), an Australian Cancer Research Fund (ACRF) grant, and Suttons Family and Len Ainsworth Foundation philanthropy and Cancer Research UK core funding at the CRUK Beatson Institute (A17196). Conceptualization, A.F. K.J.M. K.I.A. P.T. and M.N.; methodology, S.C.W. K.I.A, P.T. and M.N. investigation, A.F. K.J.M. S.L.L. A.T.M. Y-.K.L. J.S. P.M. C.S.G. X.M. V.L. A.Z. A.D.S. M.T. S.R. M.S. G.S. L.M. S.M.M. N.F. and M.N.; formal analysis, A.F. K.J.M. S.L.L. Y-.K.L. A.T.M. and M.N.; resources, S.C.W. L.M.O. A.-K.E.J. H.J.S. M.F.O. L.M.M. O.J.S, J.P.M. C.A.M. M.S.S. D.R.C. H.C.E.W. K.B. and C.E.C.; funding acquisition, D.H. K.I.A. P.T. and M.N.; writing ? original draft, P.T. and M.N.; writing ? review and editing, D.H. P.T. and M.N.; supervision, K.I.A. P.T. and M.N.; all authors critically revised the manuscript. P.T. receives reagents from Kadmon, INXMED (consultant), CRUK Astra Zeneca Alliance laboratory, RedX Pharma, Equlibre Biopharmaceuticals, and Amplia Therapeutics. Under a licensing agreement between Amplia Therapeutics and the Garvan Institute of Medical Research, K.M. D.H. and P.T. (consultant) are entitled to milestone payments. The Owen Sansom laboratory receives funding from Cancer Research Technology, Redex, Astra Zeneca, and Novartis. The remaining authors declare no competing interests. Funding Information: The authors would like to thank the staff at the Australian BioResource, Biological testing facility, tissue culture facility under G. Lehrbach and R. Lyons, the GWCCG Core facility Flow Cytometry under E. Lam and the histology core facility under the leadership of A. Zaratzian at the Garvan Institute of Medical Research. The authors would further like to thank the staff at the Biological Services Unit, Beatson Advanced Imaging Resource and histology facility under the leadership of Colin Nixon at the CRUK Beatson Institute. The FVB/NJ 8th generation clean PyMT-20065 cell line was made available through SEARCHBreast ( https://searchbreast.org/ ). Some images were adapted from Servier Medical Art, licensed under the Creative Commons Attribution 3.0. Unported license ( http://creativecommons.org/licenses/by/3.0/ ). This work was supported by a Cancer Institute New South Wales (CINSW) Early Career fellowship (M.N. and D.H.), an NHMRC Ideas grant (M.N.), NBCF grants (P.T., IIRS-21-077 ; D.H., IN-17-070 and IIRS-18-129 ), an NHMRC project grant and Senior Research Fellowship (SRF) (P.T.), St Vincent{\textquoteright}s Clinical Foundation grants (M.N., D.H., P.T., and C.E.C.), an Australian Cancer Research Fund (ACRF) grant, and Suttons Family and Len Ainsworth Foundation philanthropy and Cancer Research UK core funding at the CRUK Beatson Institute ( A17196 ). Funding Information: P.T. receives reagents from Kadmon, INXMED (consultant), CRUK Astra Zeneca Alliance laboratory, RedX Pharma, Equlibre Biopharmaceuticals, and Amplia Therapeutics. Under a licensing agreement between Amplia Therapeutics and the Garvan Institute of Medical Research, K.M., D.H., and P.T. (consultant) are entitled to milestone payments. The Owen Sansom laboratory receives funding from Cancer Research Technology, Redex, Astra Zeneca, and Novartis. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = sep,
day = "14",
doi = "10.1016/j.celrep.2021.109689",
language = "English",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "11",
}
