ABOUT THE LAB

The central aim of the Sleeman lab is to understand the process of me­tastasis and to use this knowledge to develop novel anti-cancer therapies. Working mainly on breast cancer, lung cancer and melanoma, our research currently includes studies on genetic changes and signaling pathways that promote metastasis, tumor-induced lymphangiogen­esis, dissemination via the lymphatics and therapy resistance. Another important focus is to understand the microenvironmental regulation of metastatic spread and dormancy, including how changes in the extracellular matrix composition, the induction of senescence and pro-inflammatory signaling molecules act as regulators of dis­semination and metastatic outgrowth.
In additional to being Head of Department at IBCS-BIP, Jonathan Sleeman is Professor of Microvascular Biology and Pathobiology at the University of Heidelberg, Medical Faculty Mannheim, Germany, where he is a core member of the European Center for Angiocience (ECAS). Our research is carried out at both locations. More information about our activities can be found using the link below.

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RESEARCH AT IBCS-BIP

The extracellular matrix (ECM) that surrounds cells is more than just an inert scaffold. It is a rich source of microenvironmental signals and information, and plays a major role in regulating cell behaviour through the wide range of chemical and biophysical cues it provides. Dynamic changes in the synthesis, modification and degradation of the ECM provides a further level of regulatory complexity. Our work at IBCS-BIP focuses on understanding how cells respond to and regulate the ECM microenvironment, and how this two-way flow of biological information goes awry in pathological contexts.
Focusing on the regulation of malignant progression, we are investigating how the ECM regulates cancer stem cell properties, and can thereby promote metastasis. For example, we have discovered matrix-assisted autocrine signalling as a means through which particular ECM environments dramatically reduce the diffusion of signalling molecules produced by cancer cells, and thereby foster autocrine stimulation of stemness properties[1]. These properties are dependent on autocrine signal-induced expression of the transcriptional regulators Id1 and Id3. Together with colleagues at IBCS-FMS, we have identified and patented[2] a novel class of coumarins that inhibit expression of the Id1 and Id3 proteins. Currently we are exploring the potential clinical utility of these compounds for diseases such as cancer.

Another major focus of our work concerns the ECM glycosaminoglycan hyaluronic acid (HA), which is a major regulator of the viscoelastic and hydration properties of the ECM, and which can thereby impact on cell behaviour directly, or by engaging with cell surface receptors such as CD44. Accordingly, the balance between HA synthesis and degradation is tightly regulated homeostatically, and perturbed HA metabolism contributes to many disease processes, including cancer. Increased expression of CEMIP, a secreted protein that can degrade HA, is associated with numerous diseases such as cancer, arthritis, multiple sclerosis and inflammatory bowel disease[3]. The identification of inhibitors that suppress the HA degrading activity of CEMIP therefore has the potential to find clinical application for the treatment of these diseases. We have previously identified highly sulfated hyaluronic acid[4], and more recently other sulfated polymeric hydrocarbons such as heparin and dextran sulfate as being potent inhibitors of the CEMIP hyaluronidase activity[5]. Current work focuses on understanding the role of CEMIP in resistance to targeted therapy in melanoma, and the possible clinical application of CEMIP inhibitors in diseases such as cancer and arthritis.

[1] Sedlmeier G, Al‐Rawi V, Buchert J, Yserentant K, Rothley M, Steshina A, Gräßle S, Wu R‐L, Hurrle T, Richer W, Decraene C, Thiele W, Utikal J, Abuillan W, Tanaka M, Herten DP, Hill CS, Garvalov BK, Jung N, Bräse S and Sleeman JP (2021). Id1 and Id3 Are Regulated Through Matrix‐Assisted Autocrine BMP Signaling and Represent Therapeutic Targets in Melanoma. Adv. Therap. 2000065. DOI:10.1002/adtp.202000065

[2] EP 3 760 614 B1 CHEMICAL INHIBITORS OF ID PROTEINS FOR THE TREATMENT OF CANCER AND OTHER DISEASES

[3] Domanegg K, Sleeman JP, Schmaus A. CEMIP, a Promising Biomarker That Promotes the Progression and Metastasis of Colorectal and Other Types of Cancer. Cancers (Basel). 2022 Oct 18;14(20):5093. 

[4] Schmaus A, Rothley M, Schreiber C, Möller S, Roßwag S, Franz S, Garvalov BK, Thiele W, Spataro S, Herskind C, Prunotto M, Anderegg U, Schnabelrauch M, Sleeman J. Sulfated hyaluronic acid inhibits the hyaluronidase CEMIP and regulates the HA metabolism, proliferation and differentiation of fibroblasts. Matrix Biol. 2022 May;109:173-191. 

[5] Schmaus A, Spataro S, Sallmann P, Möller S, Scapozza L, Prunotto M, Sleeman JP. A Novel, Cell-Compatible Hyaluronidase Activity Assay Identifies Dextran Sulfates and Other Sulfated Polymeric Hydrocarbons as Potent Inhibitors for CEMIP. Cells. 2025 Jan 11;14(2):101. doi: 10.3390/cells14020101.