The overarching aim of our research is to understand the biology of the epithelium, one of the most ancient tissue types, in vertebrate organs. To this end, we use the mouse mammary gland as a model and focus on two major research questions: First, what is the basis of several fundamental epithelial behavior, e.g. cell differentiation, morphogenesis, physiology in normal development and in breast cancer? Second, what is the role of the microenvironment in the above processes? What we learn in normal development can serve as a baseline to understand how and why cell behavior could go awry, leading to diseases such as cancer, thus is essential for developing novel therapeutics for treating this malignancy.

Directional migration: The epithelium has historically been considered as an immotile tissue because epithelial cells are thought to be tethered to each other and the matrix with their highly expressed adhesion proteins. Our recent work showed for the first time that vertebrate epithelium can undergo directional migration and that, compared to all other known collective migration models, it uses a novel mechanism to set up front-rear polarity and to power migration (Cell Reports, 2020). Our work thus opened up new frontiers in understanding how collective migration may be regulated in vertebrate epithelium and how it could be hijacked to promote cancer metastasis.

Physiological functions: Protein secretion is one of the most basic biological processes in cells. Proteins including hormones and enzymes, which are secreted to the extracellular environment through the endoplasmic reticulum (ER) and Golgi apparatus, participate in many physiological processes and are very important for intercellular communication. However, it remains unclear how some professionally secretory cells, such as hair cells in the ear and chief cells in the stomach, accelerate the secretion of proteins to avoid excessive accumulation of intracellular proteins. We found that Ocln plays a role in regulating protein secretion by binding to SNARE components  (PNAS, 2020). Ocln mutant milk-producing cells exhibit defective protein secretion and augmented endoplasmic reticulum stress and unfolded protein response, ultimately leading to protein expression shutdown and lactation failure in mutant mice. Our results thus shed important light on the essential physiological functions of Ocln in the vertebrate epithelium.

We recently showed that members of the Sprouty gene family modulate FGF signaling and EGF signaling in the mammary epithelium and stromal microenvironment, respectively, thus constituting a critical feedback loop of stromal-epithelial interactions (PNAS, 2016). We are currently following up on these discoveries to understand the molecular basis of stromal cells in development and in breast cancer, with the goal to develop new therapeutic interventions targeting the cancer stroma.