THE RESPONSE OF THE WILD-TYPE EPITHELIUM TO ONCOGENE- EXPRESSING CELL CLUSTERS

Abstract

In early stage cancer, oncogenic lesions exist within a largely intact epithelial tissue. At later disease stages, tumours are known to alter their proteomic and mechanical microenvironment; this changes the behaviour of wild-type fibroblasts and immune cells, aiding disease progression. However, it remains largely unknown whether early oncogenic lesions alter their local environment or the behaviour of surrounding cells. To investigate the response of wild-type epithelial cells to neighbouring oncogenic lesions, we established an early carcinoma model using Xenopus laevis embryos, creating clusters of oncogene-expressing cells within otherwise normal in vivo tissue. The surrounding wild-type epithelium responds to either kRasV12 or cMYC cell clusters with a significant increase in cell division rate. Furthermore, wild-type cell divisions close to kRasV12 clusters acquire directionality, orienting towards the cluster. Cell shape analysis indicates kRasV12 clusters induce directional tensile stress in surrounding tissue. Both the changes in mechanical stress and cell division depend on non-muscle myosin II expression in the kRasV12 cluster, suggesting the response of wild-type cells is downstream of cytoskeletal contractility in kRasV12 cells. cMYC clusters do not alter tissue mechanics and the increased division rate in surrounding cells is not dependent on myosin II, implying the wild-type cell response to cMYC clusters is likely due to a change in the chemical environment. Our results indicate deregulated cell division may occur in surrounding wild-type, as well as oncogene-expressing, epithelial cells from the very earliest stages of carcinoma.

Date of Award	1 Aug 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Keith Brennan (Supervisor) & Sarah Woolner (Supervisor)