Impact of heparanase-2 (Hpa2) and Syndecan-1 (Sdc1) on breast tumorigenesis

• Applicant: Professor Dr. Martin Götte
• Subject Area: Gynaecology and Obstetrics ; Biochemistry ; Pharmacy
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535696803

Mammalian cells express a single functional heparanase (Hpa1), an endoglycosidase that cleaves the heparan sulfate carbohydrate side chains of proteoglycans, including the cell surface proteoglycan Syndecan-1 (Sdc1). This activity results in remodeling of the extracellular matrix and cell surface glycans and enhances cell dissemination associated with tumor metastasis. Both Hpa1 and Sdc1 are upregulated in breast cancer, the most frequent malignancy in women. Pivotal work by the applicants ties the cooperative action of Hpa1 and Sdc1 not only with tumor metastasis, but with all aspects of cancer progression namely tumor initiation, growth, and chemoresistance. Unlike Hpa1, very little attention was given to heparanase 2 (=Hpa2), a close homolog of heparanase that lacks HS-degrading activity. Substantial unpublished work by the applicants suggest that Hpa2 may cooperate with Sdc1 to affect breast cancer progression via mechanisms distinct from Hpa1. We hypothesize that the close cooperation of Hpa2 and its binding partner Sdc1 represents a novel mechanism that regulates breast cancer tumorigenesis, and propose to thoroughly investigate its clinicopathological significance and mode of action. We will elucidate the mode of action and impact of Hpa2 on the pathogenesis of breast cancer through investigation of its dysregulation and prognostic impact in clinical specimens, and study the mode of action and impact of nuclear Hpa2. We will characterize the heparin/heparan sulfate-binding domains of Hpa2 as a relevant Sdc1 interaction domain, elucidate the underlying molecular mechanisms of a functional Hpa2-Sdc1 axis by characterising the impact of Sdc1 on Hpa2 trafficking and subcellular localization, and analyse Sdc1-dependent oncogenic signaling affecting Hpa2 function. Finally, we will characterize the impact of Hpa2/Sdc1 contributed by the host and the tumor microenvironment on BC progression. We will focus on the impact on the inflammatory breast cancer environment using proprietary animal models, and study the impact of the Sdc1-Hpa2 axis on the immune and angiogenic BC microenvironment in advanced in vivo-inspired 3D-bioprinted cellular models. Overall, we expect our study to substantially enhance the mechanistic knowledge on the Hpa2-Sdc1 axis specifically, and extracellular matrix-based protumorigenic mechanisms in general, as a prerequisite for a successful future pharmacological targeting of the Hpa2-Sdc1 axis in breast cancer.

• DFG Programme: Research Grants
• International Connection: Israel
• Co-Investigator: Professor Burkhard Greve, Ph.D.
• Cooperation Partner: Dr. Neta Ilan, Ph.D.
• International Co-Applicant: Professor Dr. Israel Vlodavsky, Ph.D.