Journal article

Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination

Caroline P Le, Cameron J Nowell, Corina Kim-Fuchs, Edoardo Botteri, Jonathan G Hiller, Hilmy Ismail, Matthew A Pimentel, Ming G Chai, Tara Karnezis, Nicole Rotmensz, Giuseppe Renne, Sara Gandini, Colin W Pouton, Davide Ferrari, Andreas Moeller, Steven A Stacker, Erica K Sloan



Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These find..

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Awarded by Australian National Health and Medical Research Council

Awarded by Australian Research Council

Awarded by National Cancer Institute

Awarded by Australian and New Zealand College of Anaesthetists

Awarded by National Breast Cancer Foundation


Funding Acknowledgements

We thank Prof. Bernhard Riedel, Assoc. Prof. Frederic Hollande, Prof. Steven Cole, Prof. Catherine Hill, Prof. Chris Porter, Dr Chris Langmead and members of the Sloan lab for thoughtful discussion of this research and critically reviewing the manuscript; the Monash Institute of Pharmaceutical Sciences Imaging, Flow Cytometry and Analysis Core for imaging and data analysis support; Assoc. Prof. Michael Hofman and Mr Mark Scalzo for nuclear lymphoscintigraphy imaging support; and Mr Domenic Trimboli and Dr Jon Tarry for artwork. This research was funded by the Australian National Health and Medical Research Council (1008865 and 1053535), the Australian Research Council (LE110100125), the National Cancer Institute (CA160890) and the Australian and New Zealand College of Anaesthetists (N13/002). C.P.L. is supported by a Monash Graduate Scholarship and a PhD scholarship from the Co-operative Research Centre for Cancer Therapeutics. C.K.-F. is supported by a fellowship from the Swiss Cancer League and a Monash Graduate Scholarship. J.G.H. is supported by a fellowship from the Australian New Zealand College of Anaesthetists. S.A.S. is supported by a fellowship and program grant from the Australian National Health and Medical Research Council. A.M. and E.K.S. are supported by Early Career Fellowships from the National Breast Cancer Foundation.