November 2018

Dr Gernot Walko, is a skin biologist and Lecturer in Stem Cell Biology at the University of Bath. In 2017, Dr Walko was awarded a British Skin Foundation small grant for his research,Targeting YAP/TAZ as a novel therapeutic strategy in cutaneous squamous cell carcinoma.

Here he explains in more detail about the research and what he hopes it can achieve.

Background:

Skin is a very important organ in our bodies. It protects us from infection and dehydration, and allows us to feel many different things, such as pressure or heat. In humans and other mammals, the skin has three tissue layers - the epidermis, the dermis and the subcutis (or hypodermis). The epidermis forms the surface of the skin. It is made up of several layers of specialised cells called keratinocytes.

Most of the work in the cells of our body—including keratinocytes—is done by proteins, which are a huge, varied group of molecules. Therefore, the thousands of genes expressed in a particular cell determine what that cell can do. The instructions for how to make proteins comes from genes. The process by which the information in a gene is turned into a functional protein is called gene expression. Gene expression is a tightly regulated process that allows a cell to respond to its changing environment. Only a fraction of the genes in a cell are expressed at any one time, and differences in gene expression programmes determine the distinct functions of different cell types.

In all types of cancer, some of the body’s cells begin to divide without stopping and spread into surrounding tissues. As a result of altered gene expression, cancer cells differ from normal cells in many ways that allow them to grow out of control, invade surrounding tissues and spread through the body.

Skin cancer is the most common cancer world-wide, and rates continue to rise by 2–4% each year. There are two main categories of skin cancer: melanomas and non-melanoma skin cancers (NMSCs) often now also termed keratinocyte cancers. Cutaneous squamous cell carcinoma (cSCC) is a NMSC and originates from the epidermal keratinocyte. cSCC is the second most common skin cancer in the UK and world-wide. cSCC can be cured by surgical removal if detected early. But if left untreated and the cancer cells spread to other parts of the body, no effective treatment is available. This is serious, resulting in death in 70-89% of patients.

Two proteins called YAP and TAZ contribute to initiation, progression and body-wide spread of cSCC as well as many other cancer types. YAP/TAZ work in the cell’s nucleus where they interact with many other proteins to promote the expression of genes that allow cancer cells to grow, divide, migrate and spread to other body parts. YAP/TAZ appear not to be involved in the maintenance of normal healthy epidermal tissue, but they are essential for cSCC development and progression. This makes them ideal targets to develop treatments for cSCC and other cancers.

Research interests of my lab:

How YAP/TAZ control gene expression in the nucleus represents a largely unexplored but promising area to design new modalities of therapeutic anti-cancer interventions. In our current British Skin Foundation-funded project my lab first aims to identify all the different proteins that YAP/TAZ interact with in the nucleus of normal healthy keratinocytes to control gene expression in these cells. We will then monitor how the interaction partners of YAP/TAZ change as keratinocytes become more and more abnormal during development of cSCC and eventually turn into aggressive cells that can invade neighbouring tissues. This strategy should enable us to identify and characterise cSCC-specific nuclear YAP/TAZ binding partners as novel candidate targets for the design of therapeutics to treat cSCC and other cancers.

Dr Gernot Walko, University of Bath