Heparan sulfate proteoglycans (HSPGs) are cell surface glycoproteins modified by glycosaminoglycans (GAGs), critical for fine-tunning human cell physiology. HSPGs act as multifunctional regulators of cell-to-cell communication and modulators of cellular signaling, by forming platforms that organize the activity of numerous growth factors, enzymes and structural proteins. HSPGs-regulated cellular signaling facilitates survival, proliferation and migration of cancer cells. Elevated expression of HSPGs is a hallmark of pancreatic cancer, a tumor type with the highest mortality rate of all major cancers (with a 5-year survival rate of less than 9%) and makes these proteins an intensively explored molecular targets for precision medicine approaches. To date, only two therapeutic modalities targeting HSPGs in pancreatic cancer have been reported, and their anticancer potential requires further studies. Therefore, the development of novel selective therapeutical modalities is urgently needed.
The ultimate goal of this project is to design novel precision medicine approaches for pancreatic cancer by tailoring FGF1 oligomers developed recently by us. Within this project, we will construct novel HSPGs-targeting FGF1 oligomers, HMLAs, through their uncoupling from FGFRs and re-directing them entirely to HSPGs. We expect that due to their very high affinity for heparans, HMLAs, by competing with the binding of natural growth factors/cytokines to HSPGs, will act as inhibitors of pro-tumoral HSPGs signaling in pancreatic cancer. HMLAs, due to their oligomeric state, will induce clustering of HSPGs on the cell surface, which is likely to result in endocytosis of HSPGs and subsequent lysosomal degradation. We will test whether HSPGs-targeting MLAs can trigger degradation of HSPGs, leading to reduced levels of HSPGs on the surface of pancreatic cancer cells, and thereby further eliminating the oncogenic potential of HSPGs. Next, we will explore HMLAs applicability as macromolecular drug delivery agents targeting HSPGs overproduced by pancreatic cancer cells. We will functionalize HMLAs by their covalent coupling to cytotoxic drugs and use the developed cytotoxic conjugates to eliminate pancreatic cancer cells overexpressing HSPGs. Furthermore, we will study the mechanisms of HSPGs endocytosis in pancreatic cells and use the knowledge gained to modulate endocytic processes in normal and cancerous pancreatic cells to increase the efficiency and selectivity of conjugates delivery into the tumor. The completion of this highly innovative project, in addition to its fundamental importance for cancer cell biology, may facilitate the design of novel targeted therapeutic strategies against cancers with aberrant HSPGs.
Project carried out within the OPUS-22 programme of the National Science Centre (2021/43/B/NZ1/00245)
Project duration: 2022-2026
Research Team:
Łukasz Opaliński (PhD, DSc) – project leader
Natalia Porębska (PhD)– contractor of the project
Aleksandra Chorążewska (Msc)– PhD student
Krzysztof Ciura – PhD student
Daniel Krowarsch (PhD, DSc)– contractor of the project
Małgorzata Zakrzewska (PhD, DSc) – contractor of the project
Publications:
Krzyscik MA, Porębska N, Opaliński Ł, Otlewski J, Targeting HER2 and FGFR-positive cancer cells with a bispecific cytotoxic conjugate combining anti-HER2 Affibody and FGF2, International Journal of Biological Macromolecules, 2024.
Porębska N, Ciura K, Chorążewska A, Zakrzewska M, Otlewski J, Opaliński Ł*, Protein-based strategies for generation of multivalent protein-drug conjugates-towards upgraded precision and efficiency of drug delivery into cancer cells, Biotechnology Advances, 2023.
Gregorczyk P, Porębska N, Żukowska D, Chorążewska A, Gędaj A, Malinowska A, Otlewski J, Zakrzewska M, Opalinski Ł*, N-glycosylation acts as a switch for FGFR1 trafficking between the plasma membrane and nuclear envelope, Cell Communication and Signaling, 2023.