In vivo capture and label-free detection of early metastatic cells

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Abstract

Breast cancer is a leading cause of death for women, with mortality resulting from metastasis. Metastases are often detected once tumour cells affect the function of solid organs, with a high disease burden limiting effective treatment. Here we report a method for the early detection of metastasis using an implanted scaffold to recruit and capture metastatic cells in vivo, which achieves high cell densities and reduces the tumour burden within solid organs 10-fold. Recruitment is associated with infiltration of immune cells, which include Gr1hiCD11b+ cells. We identify metastatic cells in the scaffold through a label-free detection system using inverse spectroscopic optical coherence tomography, which identifies changes to nanoscale tissue architecture associated with the presence of tumour cells. For patients at risk of recurrence, scaffold implantation following completion of primary therapy has the potential to identify metastatic disease at the earliest stage, enabling initiation of therapy while the disease burden is low.

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Figure 1: PLG scaffolds recruit metastatic tumour cells.
Figure 2: Recruitment of tumour cells to scaffolds reduces tumour burden in lung.
Figure 3: Early detection of tumour cells in scaffolds.
Figure 4: Detection of tumour cells in scaffold using ISOCT.
Figure 5: Evaluation of the immune environment within scaffolds.
Figure 6: Immunomodulation of the scaffold microenvironment influences recruitment of tumour cells.

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Acknowledgements

231BR cells and support in development of the orthotopic tumour model were provided by V. Cryns, A. Mazar and the Northwestern University Developmental Therapeutics Core. G. Bushnell provided assistance with animal studies. Whole-animal imaging was performed at the Northwestern University Center for Advanced Molecular Imaging generously supported by NCI CCSG P30 CA060553. Flow cytometry work was supported by the Northwestern University Flow Cytometry Facility and a Cancer Center Support Grant (NCI CA060553). Confocal microscopy was performed at the Northwestern University Biological Imaging Facility on a Leica TCS SP5 laser scanning confocal microscope system purchased with funds from the NU Office for Research. This research was supported by the National Institutes of Health (R01CA173745) and the Northwestern H Foundation Cancer Research Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the H Foundation. B.A.A. is the recipient of a NSF Graduate Research Fellowship.

Author information

S.M.A., R.M.G, B.A.A., E.J.J. and S.S.R., performed tumour inoculations, implantation of biomaterials, and flow cytometry studies. A.G.G. cryosectioned tissues. S.M.A., E.J.J. and Y.R. fabricated scaffolds and performed H&E staining. M.E.S. performed pathological analysis and scoring of tissue sections. S.M.A. performed immunohistochemistry and confocal imaging. B.A.A. and S.M.A. performed migration assays. J.Y. performed ISOCT imaging. S.M.A., J.Y., E.J.J. and S.L.T. Analysed data. V.B., J.S.J. and L.D.S. provided guidance and expertise. S.M.A., J.Y., V.B., J.S.J. and L.D.S. wrote and edited the manuscript.

Correspondence to Vadim Backman or Jacqueline S. Jeruss or Lonnie D Shea.

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Azarin, S., Yi, J., Gower, R. et al. In vivo capture and label-free detection of early metastatic cells. Nat Commun 6, 8094 (2015) doi:10.1038/ncomms9094

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