Mingdian Tan

All Publications

• LIF Promotes Sec15b-Mediated STAT3 Exosome Secretion to Maintain Stem Cell Pluripotency in Mouse Embryonic Development. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Xu, L., Ji, J., Wang, L., Pan, J., Xiao, M., Zhang, C., Gan, Y., Xie, G., Tan, M., Wang, X., Wen, C., Fan, Y., Chin, Y. E. 2024: e2407971

  Abstract

  LIF maintains self-renewal growth in mouse embryonic stem cells (mESC) by activating STAT3, which translocates into nucleus for pluripotent gene induction. However, the ERK signaling pathway activated by LIF at large counteract with pluripotent gene induction during self-renewal growth. Here, it is reported that in mESC STAT3 undergoes multivesicular endosomes (MVEs) translocation and subsequent secretion, LIF-activated STAT3 is acetylated on K177/180 and phosphorylated on Y293 residues within the N-terminal coiled-coil domain, which is responsible for the interaction between STAT3 and Secl5b, an exocyst complex component 6B (EXOC6B). STAT3 translocation into MVEs resulted in the downregulation of T202/Y204-ERK1/2 phosphorylation and up-regulation of S9-GSK3beta phosphorylation for maintaining mESC self-renewal growth. STAT3 with K177R/K180R or Y293F substitution fails to execute MVEs translocation and Secl5b-dependent secretion. Mice expressing K177RK180R substitution (STAT3mut/mut) are partially embryonic lethal. In STAT3mut/mut embryos, gene expressions related to hematological system function changed significantly and those living ones carry a series of abnormalities in the hematopoietic system. Furthermore, mice with Secl5b knockout exhibit embryonic lethality. Thus, Secl5b mediated STAT3 MVEs translocation regulates the balance of ERK and GSK3beta signaling pathways and maintain mESC self-renewal growth, which is involved in regulating the stability of hematopoietic system.

  View details for DOI 10.1002/advs.202407971

  View details for PubMedID 39475099

• Lipid-Based Self-Microemulsion of Niclosamide Achieved Enhanced Oral Delivery and Anti-Tumor Efficacy in Orthotopic Patient-Derived Xenograft of Hepatocellular Carcinoma in Mice. International journal of nanomedicine Liu, Y., Guerrero, D. Q., Lechuga-Ballesteros, D., Tan, M., Ahmad, F., Aleiwi, B., Ellsworth, E. L., Chen, B., Chua, M., So, S. 2024; 19: 2639-2653

  Abstract

  Introduction: We previously identified niclosamide as a promising repurposed drug candidate for hepatocellular carcinoma (HCC) treatment. However, it is poorly water soluble, limiting its tissue bioavailability and clinical application. To overcome these challenges, we developed an orally bioavailable self-microemulsifying drug delivery system encapsulating niclosamide (Nic-SMEDDS).Methods: Nic-SMEDDS was synthesized and characterized for its physicochemical properties, in vivo pharmacokinetics and absorption mechanisms, and in vivo therapeutic efficacy in an orthotopic patient-derived xenograft (PDX)-HCC mouse model. Niclosamide ethanolamine salt (NEN), with superior water solubility, was used as a positive control.Results: Nic-SMEDDS (5.6% drug load) displayed favorable physicochemical properties and drug release profiles in vitro. In vivo, Nic-SMEDDS displayed prolonged retention time and plasma release profile compared to niclosamide or NEN. Oral administration of Nic-SMEDDS to non-tumor bearing mice improved niclosamide bioavailability and Cmax by 4.1- and 1.8-fold, respectively, compared to oral niclosamide. Cycloheximide pre-treatment blocked niclosamide absorption from orally administered Nic-SMEDDS, suggesting that its absorption was facilitated through the chylomicron pathway. Nic-SMEDDS (100 mg/kg, bid) showed greater anti-tumor efficacy compared to NEN (200 mg/kg, qd); this correlated with higher levels (p < 0.01) of niclosamide, increased caspase-3, and decreased Ki-67 in the harvested PDX tissues when Nic-SMEDDS was given. Biochemical analysis at the treatment end-point indicated that Nic-SMEDDS elevated lipid levels in treated mice.Conclusion: We successfully developed an orally bioavailable formulation of niclosamide, which significantly enhanced oral bioavailability and anti-tumor efficacy in an HCC PDX mouse model. Our data support its clinical translation for the treatment of solid tumors.

  View details for DOI 10.2147/IJN.S442143

  View details for PubMedID 38500681

• Rational design, synthesis and structural characterization of peptides and peptidomimetics to target Hsp90/Cdc37 interaction for treating hepatocellular carcinoma. Computational and structural biotechnology journal Sukumaran, S., Tan, M., Ben-Uliel, S. F., Zhang, H., De Zotti, M., Chua, M. S., So, S. K., Qvit, N. 2023; 21: 3159-3172

  Abstract

  Heat shock protein 90 (Hsp90) and cell division cycle 37 (Cdc37) work together as a molecular chaperone complex to regulate the activity of a multitude of client protein kinases. These kinases belong to a wide array of intracellular signaling networks that mediate multiple cellular processes including proliferation. As a result, Hsp90 and Cdc37 represent innovative therapeutic targets in various cancers (such as leukemia, multiple myeloma, and hepatocellular carcinoma (HCC)) in which their expression levels are elevated. Conventional small molecule Hsp90 inhibitors act by blocking the conserved adenosine triphosphate (ATP) binding site. However, by targeting less conserved sites in a more specific manner, peptides and peptidomimetics (modified peptides) hold potential as more efficacious and less toxic alternatives to the conventional small molecule inhibitors. Using a rational approach, we herein developed bioactive peptides targeting Hsp90/Cdc37 interaction. A six amino acid linear peptide derived from Cdc37, KTGDEK, was designed to target Hsp90. We used in silico computational docking to first define its mode of interaction, and binding orientation, and then conjugated the peptide with a cell penetrating peptide, TAT, and a fluorescent dye to confirm its ability to colocalize with Hsp90 in HCC cells. Based on the parent linear sequence, we developed a peptidomimetics library of pre-cyclic and cyclic derivatives. These peptidomimetics were evaluated for their binding affinity to Hsp90, and bioactivity in HCC cell lines. Among them, a pre-cyclic peptidomimetic demonstrates high binding affinity and bioactivity in HCC cells, causing reduced cell proliferation that is associated with induction of cell apoptosis, and down-regulation of phosphorylated MEK1/2. Overall, this generalized approach of rational design, structural optimization, and cellular validation of 'drug-like' peptidomimetics against Hsp90/Cdc37 offers a feasible and promising way to design novel therapeutic agents for malignancies and other diseases that are dependent on this molecular chaperone complex.

  View details for DOI 10.1016/j.csbj.2023.05.023

  View details for PubMedID 37304004

  View details for PubMedCentralID PMC10250827

• Extracellular Vesicles (EVs) in Tumor Diagnosis and Therapy. Technology in cancer research & treatment Tan, M., Ge, Y., Wang, X., Wang, Y., Liu, Y., He, F., Teng, H. 2023; 22: 15330338231171463

  Abstract

  In recent years, extracellular vesicles (EVs) have gained significant attention due to their tremendous potential for clinical applications. EVs play a crucial role in various aspects, including tumorigenesis, drug resistance, immune escape, and reconstruction of the tumor microenvironment. Despite the growing interest in EVs, many questions still need to be addressed before they can be practically applied in clinical settings. This paper aims to review EVs' isolation methods, structure research, the roles of EVs in tumorigenesis and their mechanisms in multiple types of tumors, their potential application in drug delivery, and the expectations for their future in clinical research.

  View details for DOI 10.1177/15330338231171463

  View details for PubMedID 37122245

• NIR-II imaging of hepatocellular carcinoma based on a humanized anti-GPC3 antibody. RSC medicinal chemistry Shi, H., Huttad, L. V., Tan, M., Liu, H., Chua, M. S., Cheng, Z., So, S. 2022; 13 (1): 90-97

  Abstract

  Liver cancer, of which hepatocellular carcinoma (HCC) is the most common form, is one of the most lethal cancers worldwide. The five-year survival rate for HCC is below 9%, which can be attributed to late diagnosis and limited treatment options at the late stage. Therefore, safe and efficient imaging strategies are urgently needed to facilitate HCC diagnosis and stage evaluation. The development of the second near infrared window (NIR-II, 1000-1700 nm) fluorescence imaging offers the advantages of enhanced resolutions, deeper penetration depth, and less autofluorescence compared to traditional NIR-I window (700-900 nm) imaging. Herein, an HCC targeted NIR-II fluorescent probe, GPC-ICG, was developed by labelling a humanized anti-GPC3 monoclonal antibody with indocyanine green (ICG). Compared to the negative control IgG-ICG probe, the GPC3-ICG probe demonstrated specific GPC3 targeting capability in vitro. And for GPC3 positive Huh-7 tumor bearing mice, the GPC3-ICG probe specifically accumulated in subcutaneous xenografts, with a tumor-background ratio (TBR) of up to 3. The NIR-II imaging of mice organs ex vivo also indicated that GPC3-ICG specifically targeted Huh-7 tumor tissue. Overall, GPC3-ICG is a promising NIR-II probe for GPC3 targeted imaging of HCC.

  View details for DOI 10.1039/d1md00313e

  View details for PubMedID 35224499

  View details for PubMedCentralID PMC8792977

• A Humanized Anti-GPC3 Antibody for Immuno-Positron Emission Tomography Imaging of Orthotopic Mouse Model of Patient-Derived Hepatocellular Carcinoma Xenografts. Cancers Natarajan, A., Zhang, H., Ye, W., Huttad, L., Tan, M., Chua, M., Gambhir, S. S., So, S. K. 2021; 13 (16)

  Abstract

  Glypican-3 (GPC3) is an attractive diagnostic marker for hepatocellular carcinoma (HCC). We previously reported the potential of an 89Zr-labeled murine anti-GPC3 antibody (clone 1G12) for immunoPET imaging of HCC in orthotopic patient-derived xenograft (PDX) mouse models. We now humanized the murine antibody by complementarity determining region (CDR) grafting, to allow its clinical translation for human use. The engineered humanized anti-GPC3 antibody, clone H3K3, retained comparable binding affinity and specificity to human GPC3. H3K3 was conjugated with desferrioxamine (Df) and radiolabeled with 89Zr to produce the PET/CT tracer 89Zr-Df-H3K3. When injected into GPC3-expressing orthotopic HCC PDX in NOD SCID Gamma (NSG) mice, 89Zr-Df-H3K3 showed specific high uptake into the orthotopic PDX and minimal, non-specific uptake into the non-tumor bearing liver. Specificity was demonstrated by significantly higher uptake of 89Zr-Df-H3K3 into the non-blocked PDX mice, compared with the blocked PDX mice (which received prior injection of 100 mg of unlabeled H3K3). Region of interest (ROI) analysis showed that the PDX/non-tumor liver ratio was highest (mean ± SD: 3.4 ± 0.31) at 168 h post injection; this ratio was consistent with biodistribution studies at the same time point. Thus, our humanized anti-GPC3 antibody, H3K3, shows encouraging potential for use as an immunoPET tracer for diagnostic imaging of HCC patients.

  View details for DOI 10.3390/cancers13163977

  View details for PubMedID 34439132

• Impact of postoperative radiotherapy for T3N0M0 esophageal cancer patients: A population-based study. Clinical and translational medicine Ge, Y., Yin, L., Tan, M., Dai, W., Jiang, Y., Chen, L., He, X. 2020: e143

  View details for DOI 10.1002/ctm2.143

  View details for PubMedID 32722868