Dr Yuxin Cui

Trosolwg

I have been involved in cancer research starting from molecular mechanisms of arsenic trioxide induced apoptosis in acute promyelocytic leukaemia since 1999. I was also involved in a project investigating transgenic and knockout mice models of novel all-trans-retinoic-acid inducible genes. By undertaking those projects, I honed my cancer research skills including tissue culture, drug stimulation, western blotting, vector construction, molecular cloning, northern blotting, stem cell manipulation, bioinformatics and signalling pathway analysis.

Current Research

I focus on new strategies for therapeutic targeting of solid tumour metastasis. One of my current research interests is signalling transduction pathways of tumour cells in tumour micro-environment. I am particularly interested in the mechanisms of progressive cell growth associated with PSMA and MDM2. PSMA is frequently over-expressed in cancer and proposed as a pro-angiogenic protease, while MDM2 plays a regulatory role in VEGF expression and VEGF-mediated angiogenesis. Knocking-down of PSMA can down-regulate MDM2 expression as well. However, their potential synergic signalling pathways and downstream activities have not been fully elucidated. In addition, I'm also interested in the integration of the CRISPR/Cas9 genome-editing technique with new therapeutic targets. I have established this platform in lab and a couple of lead candidates are subjected to investigation in vitro and in vivo. Meanwhile, I am interested in the delivery of new microRNA therapeutics in tumour models based on our recent findings. Furthermore, I also explore how tumour cells can evade host immune responses and obtain aggressive properties. We hypothesize that by immunoediting tumour cells either self-disguise or shift the tumour-killing activities of immune cells in favour (so-called “3Es”). Conversely, the immune cells may stimulate the “evolution” of the tumours cells or promote tumour survival by infiltrating the tumour microenvironment in a chronic inflammation manner. New insight into the mechanisms of tumour interactions with the immune cells will be vital to help us develop more effective therapeutic approaches, which can ultimately exterminate cancer by arousing the original immune surveillances in patients.

Previous Research During my postdoctoral period in Cambridge, I researched the mechanisms of NPM-ALK oncogene translocation in MDM2-p53 dynamic equilibrium and downstream tumour cell signalling pathways. The majority of ALK-expressing ALCL carry wild-type p53 and do not over express MDM2, the primary E3 ubiquitin ligase for the p53. We demonstrated a novel p53-dependent pathogenetic mechanism in ALK-expressing lymphoma and confirmed NPM-ALK–induced activation of the PI 3-kinase and JNK stress-activated protein kinases. We further showed that constitutive ALK signalling leads to the functional inactivation and/or degradation of p53, which were JNK and MDM2 dependent. In ALK expressing cells, p53-induced apoptosis can be triggered by pharmacologic inhibition of JNK, PI 3-kinase and/or MDM2, suggesting a novel therapeutic modality. I researched the regulatory role of the epigenetic microenvironment in human nasopharyngeal carcinoma (NPC) cells. We demonstrated that non-side-population NPC cells co-cultured with macrophage-like cells are able to differentiate into heterologous cell sub-populations, and acquire cell cycle arrest and higher migration capacity, suggesting more aggressive characteristics. These NPC cells express a distinguished level of pluripotency-associated genes such as ARMER, PCBP1 and PDHB with response to this unique macrophage-conditioned microenvironment stimulus. Cancer will be incurable when skeletal metastasis occurs. Therefore it is crucial to understand how the bone remodelling process are mediated and disrupted under tumorigenic conditions. I previously investigated a hypothesis that mediators for osteogenesis are also involved in mediating angiogenesis and vice versa. By quantitative analysis of real-time label-free cell migration, we revealed for the first time that rhBMP-2, rhVEGF165, rhPTN and TP508 play their potent roles in stimulating angiogenesis and osteogenesis by recruiting osteoblasts and endothelial cells via chemotactic attraction. Specific inhibition of these molecules or receptors may execute therapeutic effect on cancer bone metastasis. Recently I carried out clinical trials and drug development in industrial labs following the guides of GCLP, ICH and MHRA GCP. I investigated immune tolerance and efficacy of novel immune-suppression vaccine-like drugs via immunological approaches such as patient PBMC isolation and culture, immune profiling by FACS, ex-vivo drug stimulation, T-lymphocyte proliferation and tracking, ELISPOT, multiplex cytokine measurement and high throughput data analysis. I hope I can transfer my clinical trial experience into translational cancer research.

During my postdoctoral period in Cambridge, I researched the mechanisms of NPM-ALK oncogene translocation in MDM2-p53 dynamic equilibrium and downstream tumour cell signalling pathways. The majority of ALK-expressing ALCL carry wild-type p53 and do not over express MDM2, the primary E3 ubiquitin ligase for the p53. We demonstrated a novel p53-dependent pathogenetic mechanism in ALK-expressing lymphoma and confirmed NPM-ALK–induced activation of the PI 3-kinase and JNK stress-activated protein kinases. We further showed that constitutive ALK signalling leads to the functional inactivation and/or degradation of p53, which were JNK and MDM2 dependent. In ALK expressing cells, p53-induced apoptosis can be triggered by pharmacologic inhibition of JNK, PI 3-kinase and/or MDM2, suggesting a novel therapeutic modality. I researched the regulatory role of the epigenetic microenvironment in human nasopharyngeal carcinoma (NPC) cells. We demonstrated that non-side-population NPC cells co-cultured with macrophage-like cells are able to differentiate into heterologous cell sub-populations, and acquire cell cycle arrest and higher migration capacity, suggesting more aggressive characteristics. These NPC cells express a distinguished level of pluripotency-associated genes such as ARMER, PCBP1 and PDHB with response to this unique macrophage-conditioned microenvironment stimulus. Cancer will be incurable when skeletal metastasis occurs. Therefore it is crucial to understand how the bone remodelling process are mediated and disrupted under tumorigenic conditions. I previously investigated a hypothesis that mediators for osteogenesis are also involved in mediating angiogenesis and vice versa. By quantitative analysis of real-time label-free cell migration, we revealed for the first time that rhBMP-2, rhVEGF165, rhPTN and TP508 play their potent roles in stimulating angiogenesis and osteogenesis by recruiting osteoblasts and endothelial cells via chemotactic attraction. Specific inhibition of these molecules or receptors may execute therapeutic effect on cancer bone metastasis. Recently I carried out clinical trials and drug development in industrial labs following the guides of GCLP, ICH and MHRA GCP. I investigated immune tolerance and efficacy of novel immune-suppression vaccine-like drugs via immunological approaches such as patient PBMC isolation and culture, immune profiling by FACS, ex-vivo drug stimulation, T-lymphocyte proliferation and tracking, ELISPOT, multiplex cytokine measurement and high throughput data analysis. I hope I can transfer my clinical trial experience into translational cancer research.