Intravital FLIM-FRET imaging reveals dasatinib-induced spatial control of Src in pancreatic cancer

Nobis, M. et al. (2013) Intravital FLIM-FRET imaging reveals dasatinib-induced spatial control of Src in pancreatic cancer. Cancer Research, 73(15), pp. 4674-4686. (doi:10.1158/0008-5472.CAN-12-4545)

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Publisher's URL: http://dx.doi.org/10.1158/0008-5472.CAN-12-4545

Abstract

Cancer invasion and metastasis occur in a complex three-dimensional environment, with reciprocal feedback from the surrounding host tissue and vasculature governing behavior. Here, for the first time, we have successfully analysed the spatiotemporal regulation of Src activity in response to the anti-invasive Src inhibitor dasatinib in alive animal model of pancreatic cancer using a FLIM-FRET Src-biosensor to monitor drug targeting efficacy in vivo. We show that in contrast to conventional techniques, FLIM-FRET analysis allows for accurate, time-dependent, live monitoring of drug efficacy and clearance in live tumors. In three-dimensional organotypic cultures we demonstrate that a spatially distinct gradient of Src activity exists within invading tumor cells, governed by the depth of penetration into complex matrices. In line with this, we show that this gradient also exists within live tumors, where Src activity is enhanced at the invasive border relative to the tumor cortex. Upon treatment with dasatinib we observe a switch in activity at the invasive borders, correlating with their impaired metastatic capacity in vivo. Moreover, Src regulation is governed by the proximity of cells to the host vasculature as cells distal to the vasculature are differentially regulated in response to drug treatment compared to cells proximal to vasculature. This suggests that in live tumors a threshold of drug penetrance exists and can be used to map areas of poor drug targeting efficiency within specific tumor microenvironments. Employment of FLIM-FRET in this capacity could therefore be used as a pre-clinical tool in animal models prior to clinical investigations.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Frame, Prof Margaret and Edward, Dr Michael and McGhee, Dr Ewan and McGarry, Ms Lynn and Evans, Professor Thomas and Campbell, Mr Andrew and Morton, Dr Jennifer and Quinn, Dr Jean and Schwarz, Ms Juliana and Anderson, Professor Kurt and Timpson, Dr Paul and Brunton, Dr Valerie and Karim, Ms Saadia and Sansom, Professor Owen and Nobis, Mr Max
Authors: Nobis, M., McGhee, E.J., Morton, J.P., Schwarz, J.P., Karim, S.A., Quinn, J., Edward, M., Campbell, A.D., McGarry, L.C., Evans, T.R.J., Brunton, V.G., Frame, M.C., Carragher, N.O., Wang, Y., Sansom, O.J., Timpson, P., and Anderson, K.I.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Research
ISSN:0008-5472
ISSN (Online):1538-7445

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