Content and impact of the major scientific contributions

Control of cell shape, proliferation and differentiation by the extracellular matrix (ECM). Our group was among the first to realize that the ECM plays an active role in orchestrating cellular responses to both normal and pathological situations (papers published in Cell, Nature & PNAS). The emerging concept was one of active interplay between cells and the ECM where cells synthesize matrix components which in turn dictate and regulate cell shape and function. The impact of these studies is clearly indicated by the current awareness of the ECM as a key element in the regulation of cell survival and cancer progression.

Storage of bioactive molecules by heparan sulfate proteoglycans (HSPGs). Our studies were the first to demonstrate that heparan sulfate (HS) in the ECM provides a storage depot for FGF2 and thereby regulates its bioavailability. By now, the concept of ECM as a reservoir for bioactive molecules is well recognized. Our pioneering studies in this area are regarded of prime importance to the current appreciation of the tumor microenvironment and its significance in cancer progression and treatment.

Heparanase. Our long-term research on cancer metastasis led to the cloning of a human gene encoding an endoglycosidase (heparanase) that degrades HS in the vessel wall and ECM. Our team is the pioneering and world leading group in this area of research, exemplified by numerous papers, review articles and citations focusing on heparanase structure, function and clinical significance. As a direct result of our studies heparanase advanced from being an obscure enzyme with a poorly understood function to a highly promising, novel drug target, offering new treatment strategies for various cancers and other diseases (i.e., chronic inflammation, diabetic nephropathy). We and others have solved the crystal structure of the heparanase protein, paving the way for rational design of site-directed heparanase-inhibiting compounds and neutralizing antibodies. To carry out our basic and translational research, we have generated appropriate molecular tools, cell systems and animal models (i.e., heparanase transgenic and knockout mice; PDX models) and are actively collaborating with leading scientists in Europe and the US. Notably, we collaborate with pharmaceutical companies in the development of heparanase-inhibiting compounds, of which two (Roneparstat; Pixatimod) are in phase I/II clinical trial in cancer patients. Our ongoing basic studies focus on the impact of host heparanase on cancer initiation and progression, the function of heparanase as both the ‘seed’ and ‘soil’ of tumor growth and metastasis, and its role in promoting inflammation, drug resistance and in regulating the formation of exosomes and autophagosomes. We also study the function and mode of action of heparanase-2, heparanase homolog that lacks heparanase enzymatic activity and functions as a tumor suppressor.

The results of our long-term research were published in 400 peer-reviewed scientific papers and 80 review articles in highly regarded scientific journals and books, as also indicated by 31,000 citations and an H factor of 92.