Novel Synthetic Biology Approach to Monitor Transient Tumour-Immune Cell Interaction in vivo

Supervisors: Dr Bin-Zhi Qian, Elise Cachat

Project description:
Metastasis, spreading of tumour cells to secondary organs, accounts for over 90% of death from cancer and is the number one challenge for cancer research. Mounting clinical and preclinical evidences indicate that tumour-immune cell interaction has profound effect on metastasis (Kitamura et al., 2015). Previous studies from the lead supervisor have illustrated that tumour cell interaction with macrophages, a type of innate immune cells, is critical for metastasis (Qian et al., 2011). The interaction is dynamic and complex as there are different macrophage subsets, and their pro- or anti- tumour function is differentially regulated by tissue microenvironment. Intra-vital imaging provides a powerful method to illustrate dynamic cell-cell interaction in relevant in vivo tissue environment. However, it has been challenging to record transient cell-cell interactions and interpret their effect on disease progression.

Prototype chimeric receptors have recently been developed, where engineered cells respond to contact with specific ligands presented on neighbouring cells and transmit signal accordingly (Morsut et al. 2016). Using this approach, novel synthetic receptors will be developed to detect tumour cell interaction with different subsets of macrophages that bear distinct cell surface markers, and report contact through fluorescent protein expression. Therefore, this project aims to combine the power of synthetic biology and intra-vital imaging in novel in vivo models of cancer metastasis, to illustrate dynamic interaction of tumour cells and macrophages in disease progression. Together, these tools will provide novel insight into the disease mechanism and highlight potential therapeutic strategies to effectively treat this lethal disease. 

The supervisory team provides complimentary expertise in mammalian synthetic biology (EC) and tumour-macrophage interaction and in vivo metastasis models (BZQ), to ensure the success of this multi-disciplinary project. Within this project, the student will receive extensive training in scientific research skills and analytical methods, but also acquire series of specific skills in molecular and synthetic biology, as well as skills in in vivo cancer models, including intra-vital microscopy and multi-parameter flow cytometry. The student will also master the concepts and approaches of tumour microenvironment and translational cancer research. 

- Kitamura T, Qian BZ and Pollard JW. Immune cell promotion of metastasis. Nature Review Immunology 2015. 2:73-86. 
- Qian BZ, Li J, Zhang H, Kitamura T, Campion LR, Kaiser EA, Zhang J, Snyder LA and Pollard JW. CCL2 recruits inflammatory monocytes to facilitate breast tumour metastasis. Nature 2011. 475:222-25. 
- Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM, Thomson M and Lim WA. Engineering customized cell sensing and response behaviors using synthetic notch receptors. Cell 2016. 164:780-791.