Welcome to the Le lab at National University of Singapore
and City University of Hong Kong
Our research Interests in Extracellular Vesicles (EVs)
1. Develop extracellular vesicle-based therapies for cancer treatment
Extracellular vesicles (EVs) are natural vehicles of RNAs in intercellular communication hence, they are also ideal vehicles for therapeutic RNAs. Recently, we have developed a strategy to harness EVs from red blood cells (RBCs) for delivery of RNA drugs to cancer cells. RBCs are readily available from blood banks and they release a large amount of EVs hence, it is easy to purify RBCEVs in large quantities without any expensive and labor-intensive cell culture. RBCEVs mediate robust delivery of therapeutic RNAs including antisense oligo nucleotides (ASOs), Cas9 mRNA and gRNAs to both leukemia cells and solid cancer cells for efficient miRNA inhibition and genome editing. Moreover, this delivery platform is safe as RBCEVs are devoid of DNA, growth factors, and toxic substances since human RBCs are enucleated primary cells. Our study is recently published in Nature Communications (Usman et al, 2018) and the technology has been licensed to Carmine Therapeutics. We are currently engineering RBCEVs further for specific delivery of gene therapies targeting different types of cancer as well as other diseases. We are also investigating the mechanisms that mediate the uptake and intracellular trafficking of RBCEVs. This study will help us to develop RBCEVs into a versatile drug delivery platform with high efficiency and high specificity.
Advantages of the RBCEV-based drug delivery platform (Le et al, Nature Research Bioengineering Community 2018)
2. Determine how EVs mediate the interaction of tumor cells with microenvironmental cells to promote drug resistance and cancer metastasis
Cancer is a critical disease with increasing incidence in Asia due to the increase in life expectancy and many other socioeconomic changes. In the last decades, early detection and treatment for certain types of cancers has significantly improved survival, but drug resistance and cancer metastasis remain the major cause of patient mortality. Metastasis is a multi-step process that involves the translocation of cancer cells to distant organs, and this requires tumor cells to constantly adapt to the changing microenvironments at each stage. During this process, tumor cells often release a large amount of bioactive molecules, including proteins, nucleic acids and lipids, into EVs which mediate their communication with other cells in the tumor niches and at distance sites. Although it is known that EVs secreted by tumor cells deliver bioactive molecules to various cell types, it is still unclear how these cargos alter recipient cell functions, thereby promoting metastasis. One of our research goals is to investigate the key molecular mechanisms of EV-mediated cancer communication in order to identify effective therapies against this disease. We have identified miRNAs that are abundant in EVs derived from metastatic tumor cells. One of the most abundant tumor EV miRNAs, miR-125b, is transferred to resident fibroblasts and convert these cells into cancer-associated fibroblasts which promote the proliferation and metastasis of tumor cells. Our study was published in Journal of Extracellular Vesicles (Vu and Peng et al, 2019). We are currently investigating the role of other RNAs and proteins in tumor EVs for their function in intercellular communication. This research will help us to identify and validate new targets for cancer therapeutics.
A model of miR-125b transfer from breast cancer cells to fibroblasts for activation of cancer associated fibroblasts via blocking TP53INP1 and TP53 in humans.