Control of spindle orientation by Axin in 3D intestine and liver organoid cultures


Supervising PI

Trevor Dale (website)

Project Description

Objectives

To determine whether the cancer-inducing loss of Axin1 and Axin2 proteins in the liver is mediated by changes to cell polarity.

Methodology

3D liver organoid cultures generated from mice with Cre-loxP flanked alleles of Axin1 and Axin2 will be used to study the effects of deleting both anti-oncogenes. Cell biological, biochemical and gene expression studies will be used to identify the mechanisms by which Axin loss leads to cellular transformation. A particular focus will be paid to alterations in mitotic spindle orientation since Axin and its binding partners APC, b-catenin and GSK3 have previously been shown to associate with components of the centrosomal complexes and deregulation of physiological spindle-orientation in stem cell vs. progenitor decisions has been suggested to be a key step in oncogenesis.

Collaborators

Key publications

  1. Feng GJ, Cotta W, Wei XQ, Poetz O, Evans R, Jardé T, et al. Conditional disruption of Axin1 leads to development of liver tumors in mice. Gastroenterology. 2012 Dec;143(6):1650–9.
  2. Jardé T, Evans RJ, McQuillan KL, Parry L, Feng GJ, Alvares B, et al. In vivo and in vitro models for the therapeutic targeting of Wnt signaling using a Tet-OΔN89β-catenin system. Oncogene. 2013 Feb 14;32(7):883–93.
  3. Dale T, Clarke PA, Esdar C, Waalboer D, Adeniji-Popoola O, Ortiz-Ruiz M-J, et al. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat Chem Biol. 2015 Oct 26;