TGF-β signalling in RDEB Squamous Cell Carcinoma

Contents:

• Project information
• Lay summary

Investigator: Dr Gareth Inman, Dr Andrew South

Institution: Division of Cancer Research, Medical Research Institute, College of Medicine, Dentistry and Nursing, University of Dundee.

Grant: £190,284 - (01/12/2014 – 30/11/2017)

Lay summary

Dystrophic epidermolysis bullosa (DEB) is an inherited disorder that may be dominantly (one parent passes on the faulty gene) or recessively (both parents pass on a faulty gene) inherited. The dominant form is not associated with severe clinical problems, but the recessive form (RDEB) causes the person to have fragile skin that blisters easily, heals slowly and is prone to excessive scarring. Problems can also occur in the mouth and digestive system. Another serious complication is that a high proportion of people with RDEB will develop a skin cancer called squamous cell carcinoma (SCC), which is often fatal.

All cell functioning is regulated by signals being passed within and between cells. This research group has recently shown that a specific signalling system, involving a molecule called Transforming Growth Factor- β (TGF-β), is severely disrupted in the skin of people with RDEB. In cancer, the TGF-β pathway does not function properly, so that cells start to grow and divide in an uncontrolled way, TGF-β function can also be disrupted in the cells surrounding the tumour. This is important since there is a lot of interaction between the cancer cells and the neighbouring cells (called cross-talk) that often helps the cancer cells thrive. Sometimes the cancer cells send signals to the surrounding cells to turn off the responses which would normally destroy the cancer cells, or to promote blood vessel growth, which supports and nourishes the cancer.

This group have previously shown that while the RDEB cancer cells have normal TGF-β, the surrounding cells do not. Therefore, this project is investigating whether it is the surrounding cells that support the cancer or if it is cross-talk between the cancer cells and the surrounding cells that make the cancer grow.

There are already some drugs that target TGF-β pathways in clinical use. If this project can define how the TGF-β pathways are altered in SCC in RDEB patients then it may be possible to understand how we can employ these drugs to treat EB SCC, as well as providing a basis for further understanding of cell signalling and drug development.

What is important about this research?

“We are excited to learn how cancer cells interact with their environment. With further studies we may be able to exploit this knowledge to develop treatments for EB cancer.”

Investigator Biography Dr Gareth Inman is Reader at The University of Dundee, Scotland. His primary interests are to understand the role that members of the Transforming Growth Factor Beta (TGFb) family play in cancer development and progression. His studies have focused on squamous cell carcinoma of the head, neck and skin and now involve these cancers arising in patients living with recessive dystrophic epidermolysis bullosa. By understanding TGFb’s role as both a cancer promoter and a cancer inhibitor Dr Inman hopes to develop these findings for cancer treatments.