Quantitative Biology of Wnt and R-spondin signalling in colon cancer

Colon cancer is associated with increased sensitivity to Wnt signaling. Most colon cancer cells carry a mutation which truncates the tumour suppressor protein APC, a critical relay for Wnt signalling. R-spondin is a potent stimulator of the intestinal mucosa and modulates signaling from the Wnt receptor complex.

Asymmetrical colon crypt budding
colon crypt

We are studying how R-spondin potentiates Wnt signalling. Specifically, we are determining the effects of R-spondin on the dynamics of Wnt receptor complex, β-catenin levels and locations in normal and APC-defective cells. These measurements will provide quantitative information for developing predictive (computational) models for growth factor/cytokine signalling in normal, adenoma and cancerous colon crypts.

Further reading: Tan CW, Hirokawa Y, Gardiner BS, Smith DW, Burgess AW. Colon Cryptogenesis: Asymmetric Budding. PLoS One 2013 8(10):e78519. DOI: 10.1371/journal.pone.0078519 PMID: 24205248

Team members: Tony Burgess, Maree Faux, Lauren King, Chin Wee Tan, Hui Hua Zhang, Yumiko Hirokawa, Kelvin Yip, Andrea Zhu

Modes of Notch signal transduction

Notch signalling controls colon crypt development: mature crypt cell and crypt stem cell patterning and homeostasis in all metazoans. The Notch signal transduction process appears to involve ligand binding to the extracellular domain of Notch initializing a series of proteolytic events that lead to the translocation of the Notch intracellular domain (NICD) to the nucleus, where it effects transcription. In this project we use structural and cell biology to study the differences between trans Notch signalling, i.e. when the ligand (Jagged or Delta) is on an cell adjacent  cis-inhibition where the ligand is on the same cell as the receptor.

Further reading: Sprinzak, PLoS Comput Biol 2011 7(6): e1002069; Sun, Cancer Res 2014 74(4):1091-104; Ntziachristos, Cancer Cell 2014 25(3):318-34.

Team members: Nadia Kershaw, Antony Burgess, Hui Hua Zhang, Nicole Church

Chemoprevention and targeted treatment of colon cancer

Most precancerous colon cells are hypersensitive to Wnt. We have discovered and are developing a combination of two drugs to inhibit Wnt signalling and to kill colon adenoma and colon cancer cellsWe will use mouse colonoid cultures and mouse models of colon cancer to study the formulation and delivery of the drug combination. We aim to develop a two drug  chemoprevention strategy to reduce the incidence of colon cancer in the community. We are working with medicinal chemistry  colleagues in the Chemical Biology Division to develop improved drugs for targeting mitosis and src kinases to kill  cancer cells.

Team members: Antony Burgess, Maree Faux, Janet Weinstock, Chin Wee Tan, Yumiko Hirokawa, Melanie Condron