Researchers have identified ways that mechanical stress in tissue surrounding pre-malignant cells in the skin can strongly influence the development of two common forms of skin cancer, leading to one becoming more aggressive and invasive. The researchers hope their findings will aid in predicting tumour evolution and in the development of novel therapies.
The findings were published online ahead of print in Nature (Sept. 2, 2020).
Two tumour types that originate from epidermal stem cells—basal cell and squamous cell carcinomas—were the focus of the research. On a cellular scale, the two types of carcinoma have distinct structures and appearances, the authors note.
To investigate how these different structures arose, researchers induced each type of tumour in mouse models, measuring the physical properties of the tumours and the surrounding tissue. A computer model was then used to simulate how the tumours arose and acquired their shapes.
Their findings showed that the shapes of these tumours could not be a result of the same processes that shape tumours in simple, single-layer tissues such as those in the gut.
When they began to look for features that could account for the physical differences in structure between the tumour types, the investigators found differences in a set of genes involved in setting the physical properties of the basement membrane in the skin.
“The basement membrane acts as a kind of floor that separates the tumor from the surrounding tissue,” postdoctoral fellow Vince Fiore, lead author on the paper, said in a press release. Fiore works in the laboratory of Elaine Fuchs, PhD, the Rebecca C. Lancefield Professor at The Rockefeller University's Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development in New York.
Computer models predicted that either softening the basement membrane or increasing the rate at which it is assembled would generate the buds characteristic of basal cell carcinomas. In contrast, stiffening the membrane or slowing down its assembly rate would cause the folding associated with squamous cell carcinomas.
When investigators tested the computer predictions by altering the assembly rate of the basement membrane in research animals, the simulations proved correct.
“In each case, what we predicted would happen indeed happened,” Fiore said.
Further experiments showed that in addition to the contributions of the basement membrane to tumour shape, the structure and behaviours of basal and squamous cell carcinomas are also influenced by suprabasal cells located directly above them.
Squamous cell carcinomas are characterized by a relatively stiff suprabasal roof, making it more likely that the tumours will eventually break through the basement membrane floor, escape into deeper layers of the skin and ultimately spread throughout the body. Basal cell carcinomas, whose suprabasal roof is less rigid, are more likely to stay put, rendering them more benign.
“Because epidermal stem cells make both basement membrane and overlying suprabasal cells, they control the tissue’s architecture,” said Dr. Fuchs, in the release. “However, as stem cells acquire cancer-inducing mutations that change their program of gene expression, they begin to lose control of the mechanical properties needed to keep the tissue fit and healthy.”
Identifying some of the genes that impact tumour development could lead to an ability to predict whether or not a tumour will become aggressive. These genes could also represent therapeutic targets, according to the researchers.
“With these principles in mind, you can begin to understand how tumours become malignant, and then use that knowledge to perform risk assessment or develop new therapies,” Fiore said.