PhD Scientific Days 2024

Poster Session E - Molecular Medicine 2.

Genetic Deficiency of Syk in Platelets Promotes Solid Tumor Metastasis

Text of the abstract

Background: Spleen tyrosine kinase (Syk) is mainly expressed in hematopoietic cells and plays an essential role in immune cell signaling. Oral Syk inhibitors showed promising results in clinical trials against hematological malignancies. Second generation compounds are currently being evaluated in clinical trials against solid tumors. Recent evidence indicates that platelets can contribute to cancer progression, but the molecular mechanism is still not completely understood.
Aims: This project aims to understand the role of Syk in platelets during the process of metastasis formation by solid tumors. To this end, pharmacological (Syk-selective inhibitors) and genetic approaches (platelet-specific Syk deletion in experimental mice) were used.
Methods: B16F10 malignant melanoma cells were injected into C57Bl/6 mice. Syk inhibitors, fostamatinib (R788), entospletinib (GS-9973) and lanraplenib (GS-9876) were administered by oral gavage or intraperitoneally into C57Bl/6 animals. Pf4-Cre transgenic mice were crossed with the Syk-flox animals to obtain platelet lineage-restricted Syk specific-targeted mutants (referred to as SykΔPLT mice) using the Cre-lox system. Primary tumor growth was monitored by caliper measurements. Distant organ metastasis formation was tested by processing of the lungs and GI tracts of the animals.
Results: Administration of Syk inhibitors GS-9973, GS-9876 and R788 into wild-type (WT) mice injected with B16F10 tumor cells resulted significantly increased lung and GIT metastasis formation, but caused no difference in primary tumor growth. Furthermore, lineage-specific genetic deletion of Syk in platelets strongly promoted distant organ metastasis formation. The number of melanin-rich tumor deposits were significantly increased in SykΔPLT mice compared to the WT controls.
Conclusions: Results Our results indicate a key role for Syk in platelets during the prevention of solid tumor metastasis. Understanding the role of Syk in platelets during the process of metastasis formation by solid tumor cells may help the assessment of Syk inhibitors for the treatment of non-hematological malignancies and to avoid undesirable side effects of these compounds used for the treatment of autoimmune and other autoinflammatory diseases.
Fund: SE 250+ Fellowship of SE University and ÚNKP-23-5 Fellowship of the National Research, Development and Innovation Fund.