Abstract
Radiotherapy is one of the most effective approaches to achieve tumor control in cancer patients, although healthy tissue injury due to off-target radiation exposure can occur. In this study, we used a model of acute radiation injury to the lung, in the context of cancer metastasis, to understand the biological link between tissue damage and cancer progression. We exposed healthy mouse lung tissue to radiation before the induction of metastasis and observed a strong enhancement of cancer cell growth. We found that locally activated neutrophils were key drivers of the tumor-supportive preconditioning of the lung microenvironment, governed by enhanced regenerative Notch signaling. Importantly, these tissue perturbations endowed arriving cancer cells with an augmented stemness phenotype. By preventing neutrophil-dependent Notch activation, via blocking degranulation, we were able to significantly offset the radiation-enhanced metastases. This work highlights a pro-tumorigenic activity of neutrophils, which is likely linked to their tissue regenerative functions.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 173-187 |
| Number of pages | 15 |
| Journal | Nature Cancer |
| Volume | 3 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2022 |
Funding
We thank Marco Gorghetto, Edward Hardy, David Marsh, Javier Redondo, Pierre Sikivie, Ofri Telem, Alejandro Vaquero, and Giovanni Villadoro for fruitful discussions. M.B. was supported by the DOE under Award Number DESC0007968. J.W.F. and B.R.S. were supported in part by the DOE Early Career Grant DESC0019225. This research used resources of the National Energy Research Scientific Computing Center (NERSC), a U.S. Department of Energy Office of Science User Facility located at Lawrence Berkeley National Laboratory, and the Lawrencium computational cluster provided by the IT Division at the Lawrence Berkeley National Laboratory, both operated under Contract No. DE-AC02-05CH11231. This research was supported by the Exascale Computing Project (17-SC-20-SC), a collaborative effort of the U.S. Department of Energy Office of Science and the National Nuclear Security Administration. We are grateful to N. Osborne from the Safety, Health and Sustainability Team at the Francis Crick Institute for his invaluable support during this work. We thank E. Nye from the Experimental Histopathology Unit at the Crick Institute for histological processing and advice and D. Barry from the Advanced Light Microscopy Facility at the Crick Institute for image analysis advice. We are grateful to P. Chakravarty from the Bioinformatics & Biostatistics Facility at the Crick Institute for bioinformatics support. We thank B. Snijders from the Proteomics Facility at the Crick Institute and R. Goldstone and A. Edwards from the Advanced Sequencing Facility at the Crick Institute for their technical support. We are also grateful for support from the Flow Cytometry Unit, the Cell Services Unit and the Biological Resources Unit at the Francis Crick Institute, and in particular we thank D. Poniskaitiene and T. Zverev specifically for their extended contributions to welfare monitoring of experimental mice and for performing oral gavages. We are grateful to S. Quezada for his support for the image-guided focused irradiations. We thank A. Wilkins, Clinician Scientist at the ICR and Honorary Consultant at the Royal Marsden, London, for providing critical input on the manuscript sections discussing the clinical relevance of the study. We thank R. Ferreira for critical reading of the manuscript. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (grant no. FC001112), the UK Medical Research Council (grant no. FC001112), and the Wellcome Trust (grant no. FC001112) and the European Research Council (grant no. ERC CoG-H2020-725492). The work at UCL was supported by the Radiation Research Unit at the Cancer Research UK City of London Centre Award (no. C7893/A28990).
ASJC Scopus subject areas
- Oncology
- Cancer Research
