Heparan sulfate regulates the composition of the tumor microenvironment in melanoma

• Applicant: Dr. Christian Gorzelanny
• Subject Area: Cell Biology ; Dermatology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574279710

Heparan sulfate (HS), abundantly expressed by mammalian cells, is a key regulator of the tissue microenvironment. Previous research has shown that HS modulates various cellular processes, including differentiation, migration, and proliferation. In cancer, mutations in the HS biosynthesis machinery result in altered HS structure, which affects the composition of the tumor microenvironment (TME). Our previous work demonstrated that elevated HS levels in primary melanomas promote tumor angiogenesis, increase the accumulation of pro-inflammatory cytokines and chemokines (e.g., CXCL9), and enhance the infiltration of CD8+ T cells. Clinical data further suggest that low HS expression in melanoma cells correlates with increased metastatic potential and reduced overall survival. HS biosynthesis is a complex, multistep process involving numerous enzymes that produce polysaccharide chains with considerable structural diversity and distinct biological properties. These properties are largely dictated by interactions with HS-binding proteins—including growth factors (e.g., vascular endothelial growth factor), cytokines (e.g., interferon-gamma), and chemokines (e.g., CXCL9)—which in turn are regulated by the degree and pattern of HS sulfation. The influence of HS on the TME and the relationship between its structural features and TME composition remain poorly understood. We hypothesize that the structural code of HS is crucial for tumor angiogenesis and the recruitment of tumor-infiltrating immune cells. Specifically, we propose that the HS structure directly affects tumor recognition and elimination by the immune system. Preliminary data indicate that subtle changes in HS O-sulfation significantly enhance infiltration by cytotoxic CD8+ T cells. Additional findings show that HS forms nanometric clusters on the melanoma cell surface via interactions with HS-binding proteins. These exposed clusters promote endothelial and potentially immune cell migration. Based on these observations, our project will investigate how HS and its interactions with growth factors and cytokines regulate communication with endothelial and immune cells in vitro, in addition to angiogenesis and immune cell recruitment in vivo. The project comprises four work packages (WPs): WP1: Expansion of a CRISPR/Cas9-engineered melanoma cell library featuring defined alterations in HS biosynthesis. WP2: Biochemical characterization of HS structures produced by engineered cell lines. WP3: Biological analysis of these cell lines, focusing on how HS affects haptotactic interactions with immune and endothelial cells. WP4: Use of murine melanoma models to examine how structural alterations in HS affect primary tumor development, angiogenesis, and immune infiltration. Ultimately, our findings aim to deepen our understanding of the TME and, with translational potential, improve outcomes of immunotherapies that depend on the efficient recruitment of cytotoxic immune cells to tumor tissues.

• DFG Programme: Research Grants