Understanding the role of Kindlin-1 loss in the development of squamous cell carcinoma (Brunton 2)
Completed| Project lead | Prof Valerie Brunton |
| Organisation | University of Edinburgh, Edinburgh, UK |
| Partner organizations & collaborators | Co-investigators: Dr Adam Byron (biochemistry) University of Edinburgh, Professor Albena Dinkova-Kostova (cellular medicine) University of Dundee, and Collaborator: Dr Alan Serrels (cancer / tumour microenvironment) University of Edinburgh |
| Project budget | GBP 230.271,67 |
| Start date / Duration | 01. Oct 2020 / 24 months |
| Funder(s) / Co-Funder(s) | DEBRA UK, DEBRA Austria, EB MSAP/EBEP Recommended |
| Research area | Skin cancer & fibrosis |
Publications related to the projects
Involvement of Kindlin-1 in cutaneous squamous cell carcinomaProject details
Short lay summary
Kindler syndrome (KS) is a rare skin disorder that develops early in life. People with KS have skin blistering, and develop thin or papery skin. They are also highly sensitive to ultraviolet (UV) radiation from the sun and sunburn easily. KS also increases the risk of developing a type of skin cancer called squamous cell carcinoma. KS occurs due to a genetic mutation in the FERMT1 gene. Mutations in FERMT1 results in the production of a defective protein called Kindlin-1.
Currently there is very little known about why the loss of a functional Kindlin-1 protein in the skin of people with KS increases their risk of developing squamous cell carcinoma (SCC). The group have previously carried out experiments on skin cells grown in the laboratory which has shown that loss of Kindlin-1 sensitises cells to UV radiation. To understand why this happens they will use a mouse model which mimics sun exposure to UV radiation. Using mice in which they can delete the Kindlin-1 protein from the skin, it will help identify UV induced changes that are specifically controlled by loss of Kindlin. The next stage will look at whether loss of Kindlin-1 in the skin leads to increased skin cancer formation following UV exposure
Scientific summary
The 3 aims of this project are:
Aim 1: Do changes in the tissue environment of tumours lacking Kindlin-1 contribute to their growth and metastatic spread?
Aim 2: Do Kindlin-1 binding partners (molecules that interact), regulate cancer (SCC) growth?
Aim 3: Does the loss of Kindlin-1 promote UV-induced skin cancer (SCC) formation?
DEBRA UK previously funded Professor Valerie Brunton at the University of Edinburgh towards research in Kindler Syndrome. To read more about this earlier, completed project.
Strategic relevance
Our research has uncovered important changes in the tumour microenvironment (the normal cells and molecules that surround and support the growth of tumour cells), that are controlled by Kindlin-1. By studying these changes, we hope to gain a better understanding of how we can prevent the development and progression of skin cancer in patients with Kindler syndrome.
What did this project achieve?
The project focused on assessing the effects of Kindlin-1 loss in cutaneous squamous cell carcinoma (cSCC), which is particularly aggressive in Kindler syndrome patients. The team detailed changes in the tumour-promoting capabilities induced by Kindlin-1 loss such as their ability to grow in mice and invade more than cSCC cells expressing Kindlin-1. This was reported in a latest publication in which the team showed that loss of Kindlin-1 reduced collagen deposition in tumours which was linked to an increased expression of MMP13, a metalloproteinase involved in collagen degradation. MMP13 was required for the Kindlin-1-dependent increased invasiveness of the cSCC cells. The research group also found that there was an increase in hypoxia-related genes and targets related to glycolysis in tumours which provides novel insights into how Kindlin-1 loss leads to the development of an environment that is permissive for tumour growth.
Furthermore, preliminary results addressing the effects of UV treatment in skin have shown that UV-A induces epidermal thickness, due to increased keratinocyte proliferation, and upregulated the expression of proteins involved in inflammation. Further investigations are taking place to address the effects of UV-A in skin of mice lacking Kindlin-1 as a model that resembles the environment in Kindler syndrome.