SOX18 and the intravasation of breast cancer cells

Metastasising breast cancer cells colonise distant organs, destroy their function and cause multi-organ failure. To reach distant sites within the organism cancer cells have to switch on/off a variety of molecular/biochemical mechanisms that are communicated through distinct intra- and inter- cellular signalling pathways. Hypothetically, metastasis can be attenuated at all steps of these pathways. Breast cancer cells disseminate through the lymphatic vasculature and the colonisation of the lymph nodes is a prognostic marker which determines the fate of the patient. Consequently, the prevention of lymph node metastasis is assumed to positively correlate with survival. Therefore, we focus our research on this very early step of the metastatic cascade: the intravasation of breast cancer cells trough the lymph endothelial barrier. NF-B was shown to contribute to breast cancer intravasation. However, this transcription factor is involved in a plethora of cellular processes such as inflammation and immune response and hence, the specificity of NF-B inhibition as a strategy to combat metastasis is limited. Of note, NF-B closely communicates with the transcription factor SOX18, which itself directly regulates the expression of PROX1. PROX1 determines the differentiation from venous blood vessel cells towards the lymphatic lineage and as it is not expressed in any other cell type than in lymph endothelial cells PROX1 is validated as the marker for lymphatic vessels. To this end, it is of particular importance that a prominent intravasation trigger-factor, 12(S)-HETE, strongly induces the SOX18-PROX1 axis. Moreover, SOX18 cross-talks back to NF-B. Since breast cancer cells spread through lymphatics (rather than blood circulation) SOX18 and PROX1 appear as promising targets to specifically interfere with lymph node metastasis. In this project, we propose to investigate the cross-talk between SOX18 and NF-B and the SOX18 signalling pathway with respect to lymphatic barrier intravasation. This may enable the development of anti-metastatic treatment concepts.

Breast- and colon carcinomas are amongst the most fatal in the western hemisphere due to their metastases in distant organs. Both cancer entities most frequently spread through lymphatic- and blood vessels. To provide anti-metastatic intervention strategies the elucidation of specific molecular metastasis mechanisms is mandatory. The malignant dissemination is based on complex interactions between the cancer cells and the endothelial cells of vascular walls. Therefore, we studied the contribution of lymph endothelial cells (LECs) to this process and how they allow cancer cells to cross in and out of the vessel lumen to facilitate their colonisation of distant sites. We discovered a vessel-specific mechanism by which cancer cell-secreted 12(S)-HETE disrupts the resilience of lymphatic vessels. Upon activation of the 12(S)-HETE receptors 12HETER and BLT2 in LECs, they retract and open an entry port within the vessel wall facilitating the access of adjacent cancer cells. Importantly, this mechanism involves vessel-specific components such as the transcription factors SOX18 and PROX1, which, when inhibited, prevent the disruption of the vessel barrier. Inhibition of this early step of metastasis at the LEC-level would provide high specificity with limited side effects. Furthermore, we discovered complex feed-back loops between SOX18, NF-B and FAK, which play also prominent roles in metastatic spreading, but also in other cellular processes of many cell types. Therefore, inhibition of NF-B and FAK alone is expected to exhibit severe side effects. Nevertheless, a combination of specific inhibition of SOX18 and PROX1 together with a moderate (yet less specific) inhibition of NF-B and/or FAK may provide an additional und potent strategy synergising in the limitation of metastatic spreading of cancer cells through the vasculature.