Helene Hoffmann, Martin Wartenberg, Sandra Vorlova, Franziska Karl-Schöller, Matthias Kallius, Oliver Reinhardt, Asli Öztürk, Leah S Schuhmair, Verena Burkhardt, Sabine Gätzner, Daniela Scheld, Rajender Nandigama, Alma Zernecke, Sabine Herterich, Süleyman Ergün, Andreas Rosenwald, Erik Henke
Oncogene 2024 AugBlood vessels in tumors are often dysfunctional. This impairs the delivery of therapeutic agents to and distribution among the cancer cells. Subsequently, treatment efficacy is reduced, and dose escalation can increase adverse effects on non-malignant tissues. The dysfunctional vessel phenotypes are attributed to aberrant pro-angiogenic signaling, and anti-angiogenic agents can ameliorate traits of vessel dysfunctionality. However, they simultaneously reduce vessel density and thereby impede drug delivery and distribution. Exploring possibilities to improve vessel functionality without compromising vessel density in the tumor microenvironment, we evaluated transcription factors (TFs) involved in epithelial-mesenchymal transition (EMT) as potential targets. Based on similarities between EMT and angiogenic activation of endothelial cells, we hypothesized that these TFs, Snai1 in particular, might serve as key regulators of vessel dysfunctionality. In vitro, experiments demonstrated that Snai1 (similarly Slug and Twist1) regulates endothelial permeability, permissiveness for tumor cell transmigration, and tip/stalk cell formation. Endothelial-specific, heterozygous knock-down of Snai1 in mice improved vascular quality in implanted tumors. This resulted in better oxygenation and reduced metastasis. Notably, the tumors in Snai1KD mice responded significantly better to chemotherapeutics as drugs were transported into the tumors at strongly increased rates and more homogeneously distributed. Thus, we demonstrate that restoring vessel homeostasis without affecting vessel density is feasible in malignant tumors. Combining such vessel re-engineering with anti-cancer drugs allows for strategic treatment approaches that reduce treatment toxicity on non-malignant tissues. © 2024. The Author(s).
Helene Hoffmann, Martin Wartenberg, Sandra Vorlova, Franziska Karl-Schöller, Matthias Kallius, Oliver Reinhardt, Asli Öztürk, Leah S Schuhmair, Verena Burkhardt, Sabine Gätzner, Daniela Scheld, Rajender Nandigama, Alma Zernecke, Sabine Herterich, Süleyman Ergün, Andreas Rosenwald, Erik Henke. Normalization of Snai1-mediated vessel dysfunction increases drug response in cancer. Oncogene. 2024 Aug;43(35):2661-2676
PMID: 39095583
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