Human skin organoids, a novel host for cancer grafts

Around 45.000 mice a year are used for oncology testing in Austria. In this project we propose to replace the use of mouse skin grafting by application of a new method, which is based on the generation of human skin by differentiating of embryonic stem cells into skin-organoids. We already succeeded in growing a single human stem cell into a complex human skin tissue composed of keratinocytes, melanocytes, fibroblasts, neurons and adipocytes. We propose that the human skin, cultured in the lab, will be ideal for testing of the behavior of malignant human skin tumor cells after grafting of those cells. We will then visualize tumor growth by live microscopy of tumor organoids and we will also apply traditional histologic tissue analysis. Our novel model represents a valuable tool for basic science in order to investigate mechanisms of melanoma progression, but it also serves translational science in order to identify better treatment options for melanoma patients. We hope that with this project we can reduce animal suffering, while at the same time leverage our knowledge on skin tumor growth.

New Frontiers in Melanoma Research: Human Skin Organoids Revolutionize Cancer Therapy Development. Summary of Research Findings A research team led by Mario Mikula and Markus Hengstschläger has deciphered crucial mechanisms driving the progression of malignant melanoma across three recent studies. The researchers identified three distinct molecular "switches" that control tumor growth and the cancer's ability to evade the immune system: NLGN4X & HIF1A: They discovered that the loss of the protein NLGN4X in late stages allows cancer cells to adapt to low-oxygen environments and migrate more aggressively. Rictor-AKT & Immune System: Blocking the AKT signaling pathway enhances the body's own immune response and boosts the efficacy of modern immune therapies (Anti-PD-L1). SR-B1 & Cholesterol: The cholesterol transporter SR-B1 protects melanoma cells during chemotherapy by modulating inflammatory signals and ensuring cell survival. Skin Organoids Instead of Animal Testing At the heart of all three projects was a technological highlight: 3D skin organoids grown in the lab from human pluripotent stem cells. How were they used? Instead of injecting tumor cells into mice, human melanoma cells were transplanted directly into this lab-grown, human-engineered skin. These organoids simulate the complex architecture and layers of human skin far more accurately than simple cell cultures in a petri dish. Why were they used? Melanomas often behave differently in human tissue than in rodents. By using organoids, researchers could observe the interaction between cancer cells, the surrounding tissue, and potential drugs in a purely human system. This increases the reliability of the results for future patient applications. Contribution to Animal Welfare (3Rs Principle) The consistent use of these organoid models makes a significant contribution to reducing animal suffering: Replacement: Many experiments that previously required living animals can now take place entirely in the lab using human tissue models. Reduction: Since the effectiveness of drugs or genetic modifications can be precisely tested at an early stage in the organoid, the number of necessary validation tests in animal models is drastically reduced. Precision: Because the models are of human origin, research errors-which could otherwise lead to unnecessary animal testing based on false hypotheses-are avoided. This research impressively demonstrates that medical progress and modern animal welfare can go hand in hand by using innovative biotechnologies to bridge the gap between the lab bench and the patient's bedside.