Epithelial cells are a major cell type that line tissues and organs and are the cell type of origin for the majority of solid cancers in humans. The development of epithelial tissues requires the cooperation of multiple cellular processes including cell proliferation, apoptosis, stem cell renewal, differentiation, oriented cell divisions, cell-cell and cell-matrix adhesions, and cell motility. Importantly, many of the same processes that are essential for developmental morphogenesis are drivers of tumour initiation, progression, and metastasis to distant organs. This progression is associated with dramatic remodelling of the epithelium and the surrounding microenvironment, and as such, we consider tumourigenesis as a special form of morphogenesis.

A primary requirement for normal epithelial function is the proper intracellular and multicellular organization, which is established and maintained by conserved groups of polarity proteins. Many of these proteins have been implicated in stem cell renewal, differentiation, directional cell motility, cell adhesion, proliferation and survival.  Furthermore, their expression is frequently altered in human cancers. Our lab is interested in understanding the molecular mechanisms by which polarity complexes regulate epithelial remodelling during normal development and cancer progression.

3D projection of a branching mammary ‘organoid’ in culture and stained for actin (red), smooth muscle actin (blue), and GFP (green).

Fluorescent micrograph of a whole-mount mammary duct immunostained for cytokeratin 8

Multiphoton micrograph of mammary tumour cells (green, direct fluorescence) with collagen (red, second harmonic generation).

Confocal micrograph of a mammary tumour section immunostained for Notch (red), GFP (green), and nuclei (blue)

Current Projects

  1. 1.Cell polarity and epithelial morphogenesis – We are interested in understanding how cell polarity proteins remodel the epithelium during branching morphogenesis, using the mammary gland as a model. Our group uses lentivirus-RNAi and a mammary transplant model to understand the in vivo functions of polarity proteins during epithelial tube morphogenesis. As a complimentary approach, we also use time-lapse confocal microscopy of 3D organoid cultures derived from mammary glands. These cultures retain many features of the intact tissue, including the presence of multiple cell types and the ability to form branched ducts. Using these approaches we have identified an essential role for the Par3/aPKC polarity complex in stem/progenitor differentiation and mammary organization.

  1. 2.Stem cell renewal – Proper control of stem cell renewal is essential for normal epithelial development and maintenance. Furthermore, cancer stem cell renewal may contribute to tumour resistance and recurrence following treatment. Our laboratory is studying how polarity complexes regulate self-renewal through symmetric and asymmetric cell divisions in normal and cancer stem cells.

  1. 3.Tumour initiation, invasion, and metastasis – Accumulating evidence indicates that a common characteristic of malignant transformation is the loss of epithelial polarity and tissue organization. Our research is focused on understanding what components of epithelial polarity are disrupted as breast cancer progresses. Using syngeneic mouse models, we examine how disrupting specific cell polarity proteins cooperates with oncogenes to drive cancer progression and metastasis.