Abstract
Elevated platelet count is associated with poor survival in certain solid cancers, including lung cancer. In addition, experimental transplantation of cancer cell lines has uncovered a role for platelets in blood-borne metastasis. These studies, however, do not account for heterogeneity between lung cancer subtypes. Subsequently, the role of platelets in the major subtypes of non-small cell lung cancer (adenocarcinoma (ADC) and squamous cell carcinoma (SqCC)) is not fully understood. We utilised an autochthonous KrasLSL-G12D/+;p53flox/flox mouse model of lung ADC together with genetic models of thrombocytopenia to interrogate the role of platelets in lung cancer growth and progression. While thrombocytopenia failed to impact primary tumour growth, in experimental metastatic models however, thrombocytopenic mice displayed significantly extended survival. Utilising a novel thrombocytopenic immunocompromised mouse, the importance of platelets in metastatic dissemination was confirmed with human KRAS-mutant ADC cell lines. Finally, retrospective analysis of a NSCLC patient cohort revealed thrombocytosis was predictive of poor survival in ADC patients with metastatic disease. Interestingly, this association was not apparent in SqCC patients. Overall, these data highlight the possibility of patient stratification using thrombocytosis as a biomarker, and indicates opportunities for potential novel treatment strategies that combine anti-platelet and lung cancer therapies.
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Data availability
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. Additional methods can be found in the supplementary information.
Code availability
All code used for analysis of lung tumour burden and HMGA2 positive staining cells is available from GitHub (https://github.com/SR-H/Image-analysis-code.git).
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Acknowledgements
We thank Prof Benjamin Kile for generously providing Bcl-xPlt20 mice and A/Prof Marie-Liesse Asselin-Labat for kindly sharing cell lines. We thank Janelle Lochland, Dr Amanda Au, Nicole Lynch, Stephanie Bound, Keti Stoev, Rebekah Meeny and Shannon Oliver for outstanding assistance and Prof Doug Hilton for helpful discussions. Ann Officer facilitated data collection for the Thoracic Malignancies Cohort Study and Him Ahmad assisted with patient pathology data collation. This work was supported by Australian National Health and Medical Research Council Project, Ideas, and Program Grants (1079250 ECJ, 1113577, 1122783 APN, 1186575 MJH, 1159658 MJH), Fellowships (1058344 WSA, 1156095 MJH), an Independent Research Institutes Infrastructure Support Scheme Grant (9000220), and a Victorian State Government Operational Infrastructure Support Grant. ECJ is the recipient of a fellowship from the Lorenzo and Pamela Galli Charitable Trust. SRH is the recipient of an Australian Postgraduate Award from the University of Melbourne. KDS is supported by a Victorian Cancer Agency Mid-Career Fellowship (MCRF18003) and the Peter and Julie Alston Centenary Fellowship. The generation of the NSG Mpl−/− mice was supported by the Australian Phenomics Network, the Leukemia and Lymphoma Society (LLS SCOR 7001-13 MJH), and the Australian Government through the National Collaborative Research Infrastructure Strategy program.
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SRH designed and performed research, analysed data, prepared figures, and wrote the paper. ECJ conceived, designed and supervised research, and wrote the paper. MA, AT, AK, AJK, MJH, JC, PG and APN conducted experiments and analysed data. KDS provided the inducible ADC model. WSA and KDS designed research and revised the paper. KDS, WSA, BS, MA, AT and APN contributed to intellectual discussions of the data. All authors reviewed the paper.
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BJS has served on advisory boards for AstraZeneca, Roche/Genentech, Pfizer, Merck, Bristol Myers Squibb, Novartis, Gritstone Oncology, Loxo Oncology.
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Analysis of human clinical data was performed according to National Statement on Ethical Conduct in Human Research and was approved by the Peter MacCallum Cancer Centre ethics committee (approval no.17/136R). All mice were handled in accordance with approved protocols (Walter and Eliza Hall Institute Animal Ethics Committee).
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Hyslop, S.R., Alexander, M., Thai, A.A. et al. Targeting platelets for improved outcome in KRAS-driven lung adenocarcinoma. Oncogene 39, 5177–5186 (2020). https://doi.org/10.1038/s41388-020-1357-6
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DOI: https://doi.org/10.1038/s41388-020-1357-6
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