Our lab explores the biochemical activities of carbohydrate processing enzymes involved in cancer progression and metastasis, thereby guiding the development of therapeutic and diagnostic molecules or tools for various types of cancers. The interdisciplinary program integrates organic chemistry, molecular and cellular biology, and molecular imaging. Our current research centers on a key enzyme called heparanase, and we are developing molecular probes to study the precise modes of heparanase activity using molecular imaging; we are also developing diagnostic tools for cancers with high metastatic potential; meanwhile we are developing new chemistries to enhance efficiency of imaging and therapy.
PART 1. Probing the role of heparanase in cancer progression via molecular imaging
Metastatic potential of cancer cells is closely related to a group of enzymes that are responsible for the remodeling and degradation of extracellular matrix (ECM). ECM is composed of an array of interwoven fibrous proteins and glycosamineglycans, such as heparan sulfate proteoglycans (HSPGs). HSPGs, consisting of several linear heparan sulfate chains covalently linked to a protein core, exist ubiquitously in the ECM of various cell types of both vertebrate and invertebrate tissues. HSPGs bind to a range of proteins in ECM and are essential in maintaining ECM self-assembly and integrity. Besides, many growth factors, chemokines, cytokines and enzymes are associated to ECM and the cell surface through binding with heparan sulfate. Cleavage of heparan sulfate chains leads to disassembly of the ECM as well as basement membrane beneath epithelial and endothelial cells, which eventually results in loosened ECM barrier and cell dissemination for metastasis.
Heparanase, endo-β-D-glucuronidase, can cleave heparan sulfate (HS) side chains of HSPGs to generate biologically active carbohydrate fragments. Importantly, heparanase is the only known enzyme for HS cleavage, and is a key enzyme involved in the ECM degradation and disassembly Despite the clinical significance of heparanase in cancer progression and inflammatory disorders, the precise mode of heparanase action remains to be elucidated due to lack of molecular tools. We hypothesize that heparanase cleaves HS side chains in a programmed manner – certain HS cleavage leads to cell dissemination, while cleavage of other specific HS structures is in charge of release of specific signaling molecules, or homeostasis of HSPGs . The current research focuses on the development of a set of molecular tools to map various roles that heparanase plays during cancer progression and metastasis. These structurally defined probes incorporate strategies to retain the readout signals at site of heparanase action to achieve high spatial resolution and precision. We will use these molecular probes to test our hypothesis in cancer models, and to study the structurally defined role of heparanase during ECM remodeling using molecular imaging both in vitro and in vivo. Understanding these precise modes is important not only for revealing the unknown role of heparanase during the remodeling of extracellular matrix, but also for better design of heparanase targeted diagnostic and therapeutic molecules for various diseases including cancer.
PART 2. Developing diagnostic tools for cancer detection and therapy response monitoring
Due to the high mortality of metastasis-associated cancers, detection of cancer lesions with metastatic potential (before metastasis occurs) offers tremendous value in the diagnosis, prognosis and management of cancer. Imaging molecular biomarkers provides molecular level specificity and sensitivity that can outcompete the traditional cancer detection methods, such as X-ray, ultrasound and MRI. Since metastatic potential of cancer cells is closely related to heparanase activity, imaging probes for heparanase and its closely related effector molecules in the signaling network therefore hold tremendous potential in medical imaging of cancer.
Heparanase plays a regulatory role in cancer development; it accelerates the growth of primary tumor, and promotes establishment of blood and lymphatic vasculature to facilitate invasion. Increased heparanase activity is mostly linked with increased tumor metastasis, higher microvessel sensitivity and shortened post surgery survival. Different from proteases (often complicated by substrate cross-reactivity) involved in ECM disassembly, heparanase is the only enzyme that can cleave heparan sulfate, therefore heparanase-targeted therapeutics and diagnostics have better selectivity in heparanase expressing tissues. Given the strong correlation of heparanase activity and metastatic potential of cancers, imaging the activity of heparanase is a promising approach to visualizing tumors with high metastatic potential. However, no molecular probe currently exists for in vivo imaging of heparanase activity, and detection of heparanase activity has only been performed using in vitro assays. We aim to develop and evaluate new positron emission tomography (PET) and magnetic resonance imaging (MRI) probes for imaging of heparanase in various human tumors. Ideally, heparanase-targeted PET and MRI tracers can profoundly enhance the practice of clinical oncology.
PART 3. Developing novel in situ activation-reactions for imaging and therapy
Imaging probes that are translatable to clinical use needs to address several criteria: 1) high sensitivity of the imaging modality, 2) highly specific interaction of the imaging probe with the cancer lesion, and 3) high signal-to-background ratio. To develop effective imaging strategies for desired targets in Parts 1 and 2, my research is also directed to explore various molecular scaffolds and smart chemistries. We have been developing novel in situ labeling bioconjugation chemistries to facilitate enzyme imaging.
Our work is supported by
Our work is supported by