A5076864927- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- RNA modifications and cancer
- Chronic Myeloid Leukemia Treatments
- Pluripotent Stem Cells Research
- Pancreatic function and diabetes
- Acute Myeloid Leukemia Research
- Developmental Biology and Gene Regulation
- Protein Degradation and Inhibitors
- Congenital heart defects research
- Adipose Tissue and Metabolism
- Ubiquitin and proteasome pathways
- TGF-β signaling in diseases
- Immune cells in cancer
- Glutathione Transferases and Polymorphisms
- CRISPR and Genetic Engineering
- Neuroscience of respiration and sleep
- Retinoids in leukemia and cellular processes
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Renal and related cancers
- Pancreatic and Hepatic Oncology Research
- Phagocytosis and Immune Regulation
- Chronic Lymphocytic Leukemia Research
- Cancer-related Molecular Pathways
Duke-NUS Medical School
2017-2025
National University of Singapore
2011-2023
National University Cancer Institute, Singapore
2011-2023
Karolinska Institutet
2012
Australian Research Council
2012
The University of Adelaide
2012
Monash University
2012
Genome Institute of Singapore
2009-2011
Agency for Science, Technology and Research
2011
Imperial College London
2007-2009
How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned developmental biology to rapidly reconstitute liver progenitors human pluripotent stem cells (hPSCs). Mapping the formation of multiple lineages revealed how alternate fates (e.g., pancreas intestines) restricted during commitment. Human fate was encoded by combinations inductive repressive extracellular signals at different doses....
Transforming growth factor-β (TGF-β) signaling is controlled by a variety of regulators that target either receptors or activated Smad complexes. Among the negative regulators, Smad7 antagonizes TGF-β mainly through targeting receptors, whereas SnoN and c-Ski repress at transcriptional level inactivation We previously found Arkadia positive regulator induces ubiquitin-dependent degradation its C-terminal RING domain. report here in addition to Smad7. interacts with their free forms as well...
Embryonic stem (ES) cells continuously decide whether to maintain pluripotency or differentiate. While exogenous leukemia inhibitory factor and BMP4 perpetuate a pluripotent state, less is known about the factors initiating differentiation. We show that heparan sulfate (HS) proteoglycans are critical coreceptors for signals inducing ES cell Genetic targeting of NDST1 NDST2, two enzymes required N-sulfation proteoglycans, blocked This phenotype was rescued by HS presented in trans soluble...
Notch signaling is frequently hyperactivated in breast cancer, but how the enhanced contributes to tumor process less well understood. In this report, we identify proinflammatory cytokine interleukin-6 (IL-6) as a novel target cells. Enhanced upregulated IL-6 expression, leading activation of autocrine and paracrine Janus kinase/signal transducers activators transcription signaling. upregulation was mediated by non-canonical signaling, it could be effectuated cytoplasmically localized...
Abstract Facioscapulohumeral muscular dystrophy (FSHD) represents a major unmet clinical need arising from the progressive weakness and atrophy of skeletal muscles. The dearth adequate experimental models has severely hampered our understanding disease. To date, no treatment is available for FSHD. Human embryonic stem cells (hESCs) potentially represent renewable source muscle (SkMCs) provide an alternative to invasive patient biopsies. We developed scalable monolayer system differentiate...
Nodal and Activin are morphogens of the TGFbeta superfamily signaling molecules that direct differential cell fate decisions in a dose- distance-dependent manner. During early embryonic development Nodal/Activin pathway is responsible for specification mesoderm, endoderm, node, mesendoderm. In contradiction to this drive towards cellular differentiation, also plays important roles maintenance self-renewal pluripotency epiblast stem cells. The molecular basis behind interpretation gradients...
Endoplasmic reticulum stress from unfolded proteins is associated with the proliferation of pancreatic tumor cells, making many regulatory molecules this pathway appealing targets for therapy. The objective our study was to assess potential therapeutic efficacy inhibitors protein response (UPR) in cancers focusing on IRE1α inhibitors. IRE1α-mediated XBP-1 mRNA splicing encodes a transcription factor that enhances chaperone order reverse UPR. Proliferation assays using panel 14 cancer cell...
Abstract Adaptation to hypoxia, a hallmark feature of many tumors, is an important driver cancer cell survival, proliferation and the development resistance chemotherapy. Hypoxia-induced stabilization hypoxia-inducible factors (HIFs) leads transcriptional activation network hypoxia target genes involved in angiogenesis, growth, glycolysis, DNA damage repair apoptosis. Although targets have been characterized, alternative splicing transcripts that occurs during roles they play oncogenesis are...
Regulation of transforming growth factor-beta (TGF-beta) signaling is critical in vertebrate development, as several members the TGF-beta family have been shown to act morphogens, controlling a variety cell fate decisions depending on concentration. Little known about role intracellular regulation pathway development. E3 ubiquitin ligases target specific protein substrates for proteasome-mediated degradation, and are implicated signaling. We that Arkadia, nuclear RING-domain ligase,...
Terminal differentiation of mammalian erythroid progenitors involves 4-5 cell divisions and induction many important genes followed by chromatin nuclear condensation enucleation. The protein levels c-Myc (Myc) are reduced dramatically during late stage maturation, coinciding with cycle arrest in G(1) phase enucleation, suggesting possible roles for either or both these processes. Here we demonstrate that ectopic Myc expression affects terminal maturation a dose-dependent manner. Expression...
Hypoxia promotes stem cell maintenance and tumor progression, but it remains unclear how regulates long-term adaptation toward these processes. We reveal a striking downregulation of the hypoxia-inducible histone H3 lysine 9 (H3K9) demethylase JMJD1A as hallmark clinical human germ cell-derived tumors, such seminomas, yolk sac embryonal carcinomas. Jmjd1a was not essential for self-renewal played crucial role suppressor in opposition to hypoxia-regulated oncogenic H3K9 methyltransferase G9a....
Clinical risk scores in chronic myeloid leukemia (CML) are inadequate for identifying phase (CP) patients at high-risk of blast crisis (BC) progression. The lack accurate predictive tests hamper timely interventions, including stem cell transplants, that more effective early disease. By interrogating a single atlas primary imatinib resistance BC-like gene expression signature, we identify aberrant CD42A+ megakaryocytic and CD10+CD19+ lymphoid progenitor expansion, as well STAT1- IFNγ-related...
Hypoxia-inducible factor-2α (HIF-2α, or EPAS1) is important for cancer progression, and a putative biomarker poor prognosis non-small cell lung (NSCLC). However, molecular mechanisms underlying the EPAS1 overexpression are not still fully understood. We explored role of single nucleotide polymorphism (SNP), rs13419896 located within intron 1 gene in regulation its expression. Bioinformatic analyses suggested that region including SNP plays expression alters binding activity transcription...
The Transforming Growth Factor (TGF) beta signalling family includes morphogens, such as Nodal and Activin, with important functions in vertebrate development. concentration of the morphogen is critical for fate decisions responding cells. Smad2 Smad3 are effectors Nodal/Activin branch TGFbeta signalling: they activated by receptors, enter nucleus directly transcribe target genes. However, there have been no studies correlating levels Smad2/3 activation expression patterns endogenous genes a...
The PIAS4 protein belongs to the family of inhibitors activated STAT, but has since been implicated in various biological activities including post-translational modification known as sumoylation. In this study, we explored roles pancreatic tumourigenesis. expression levels cancer cells were examined. Cell proliferation and invasion was studied after overexpression gene silencing PIAS4. effect on hypoxia signalling investigated. overexpressed compared with normal pancreas. Gene by small...
// Shojiro Kitajima 1, 2 , Kian Leong Lee 3 Hiroki Hikasa 4 Wendi Sun 5 Ruby Yun-Ju Huang 1 Henry Yang Shinji Matsunaga Takehiro Yamaguchi Marito Araki 6 Hiroyuki Kato and Lorenz Poellinger 7, * Cancer Science Institute of Singapore, National University Singapore Pharmacology, Graduate School Medicine, Osaka City University, Osaka, Japan Stem Cell Biology Program, Duke-NUS Medical School, Department Biochemistry, The Occupational Environmental Health, Kitakyushu, Biological Sciences, Nanyang...
This study is an unbiased genomic screen to obtain functional targets for increased effectiveness of dasatinib in pancreatic cancer. Dasatinib, a multi-targeted tyrosine kinase inhibitor, used clinical trials treatment cancer; however, intrinsic and acquired resistance often occurs. We dasatinib-resistant cancer cell line SU8686 synthetic lethality that synergizes with using pooled human shRNA library followed by next generation sequencing. Novel genes were identified which when silenced...