Poster Presentation 31st Lorne Cancer Conference 2019

Reducing platelet count or function improves disease outcome in models of metastatic lung adenocarcinoma (#205)

Stephanie R Hyslop 1 2 , Ariena Kersbergen 3 , Kate D Sutherland 1 3 , Warren S Alexander 1 2 , Emma C Josefsson 1 2
  1. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
  2. Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  3. ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia

Platelets are essential for haemostatic maintenance, however, mounting evidence suggests a further role in cancer progression. As the leading cause for cancer death in Australia, lung cancer is a major public health issue and therefore developing improved treatment options is of high importance. In this study, we have used sophisticated lung cancer models to assess the role of platelets in lung adenocarcinoma (ADC) progression. 

Mutations in KRAS and TP53 commonly occur in ADC patients. We have used mice with conditional mutations in these genes to initiate the development of tumours mimicking human ADC histopathology. Transplanting cell lines derived from these tumours intravenously into mice genetically engineered to have thrombocytopenia (low platelet count), we observed a significant survival advantage in the thrombocytopenic mice, compared to wild type (WT).

Similarly, following i.v. transplant of human ADC cell lines (A549 and H358) into NOD-scid IL2rγnull (NSG) mice and a novel NSG thrombocytopenic mouse, we observed reduced metastatic burden in the thrombocytopenic NSG mice. Notably, reduced platelet count did not impact primary tumour growth following subcutaneous transplant of murine ADC cells. Together, these results demonstrate a role for platelets in advancing ADC haematogenous metastasis, but not primary growth.

Finally, we detected a two-fold increase in platelet granule protein P-Selectin in serum from tumour bearing WT mice compared to healthy controls, indicating platelet activation has occurred. Based on this, we treated mice inoculated with murine ADC cells with clopidogrel to inhibit platelet activation. Reduced metastatic burden was observed in the treated mice, indicating that activation is required for platelets to effectively support metastasis.

Together, these data demonstrate a link between platelet activation and ADC progression, and provide further evidence for the significance of platelets in metastatic ADC. Moreover, we have shown that disrupting platelet activation also disrupts haematogenous metastasis. This provides an opportunity for future exploration of combining anti-platelet agents and conventional lung cancer therapies to increase treatment efficacy.