A new study from Tel Aviv University explains how skin cancer spreads - and how to stop it

The researcher, Dr. Carmit Levy, was looking for an answer to the question of what causes the cancer cells in the epidermis to penetrate the dermis and from there into the blood circulation. The results of the new study were published this weekend in the journal Molecular Cell

A new study from Tel Aviv University offers hope for an effective drug treatment for melanoma, the most common and deadly skin cancer. The results of the new study were published at the end of the week in the journal Molecular cells.

Melanoma is a type of cancer caused by the uncontrolled division of melanocytic cells in the skin. The melanocytic cells are found in the epidermis layer (the top layer of the skin) and are responsible for the production of melanin - a pigment that absorbs radiation at short wavelengths and thus protects the skin from dangerous exposure to the sun. Melanoma is the deadliest of skin cancers, and in developed countries the number of patients with the serious disease increases every year.

"Melanoma develops in two stages," explains Dr. Carmit Levy from the Sackler Faculty of Medicine at Tel Aviv University, who headed the team of researchers. "In the first stage, the cancer cells multiply in the epidermis, that is, in the outer layer of the skin. If the tumor is diagnosed at this time, it can be removed above the skin in a simple medical procedure. In the second stage, the cancer cells penetrate into the dermis - and from there into the blood vessels. Through the blood circulation, the cancer can anchor and create a cancerous metastasis in different parts of the body."

The question that interested Dr. Levy is what causes the cancer cells in the epidermis to penetrate the dermis. "This is a question that until today was completely open," says Dr. Levy. "But then I noticed something. In all the classic imaging images of the development of melanoma, the kind you find in any Google search, you see something strange: the cancer cells first rise up, towards the surface of the skin, and only then penetrate into the blood vessels. but why? Why does cancer invest the energy in this initial rise? Why not dive straight into the dermis and blood vessels?"

Why do cancer cells go up on their way down?

So Dr. Levy decided to investigate the skin. "I wanted to study the skin itself - what does 'dermis' and 'epidermis' mean, what exactly do these tissues consist of? That's how I learned that the epidermis is made up of layers that differ from each other in many ways, and I thought that maybe the cancer cells don't just 'rise up' at first, but as they go up, the cancer cells change the environment of their neighboring cells and maybe there they get something - something without which they won't be able to penetrate the blood vessels later and metastasize, that is, become a metastatic cancer."

To test her theory, Dr. Levy collected healthy skin tissues and separated them into all the different skin layers. After that, Dr. Levy mixed the different skin layers together with the cancer cells, in order to test the expression of the genes (Gene Expression) of the melanoma. The results confirmed the theory: the meeting between the melanoma and the upper layer of the epidermis is what makes skin cancer malignant.

"You have to understand that there are many genes that are not expressed in normal cells," explains Dr. Levy. "When the cancer cells reach the upper layer of the epidermis, this is essentially a new environment for them. In this environment, they bind to keratinocytes - cells that are at a particularly high level of differentiation in the upper epidermis layer and are responsible, among other things, for the production of keratin. This molecular relationship leads to the activation of the Notch signal, a signal that activates dormant genes in the cancer cells, changes their shape and allows them to migrate - thus penetrating the blood vessels. This is a genetic domino effect, the result of which is malignant cancer."

Dr. Levy's discovery is not only a research breakthrough, but also clinical hope. "This signal exists in many cells, and there is a drug known as DAPT, which inhibits its activation. We used it in culture on the melanoma cancer cells, and it worked: the connection was blocked, the Notch signal was not activated and the cancer did not become metastatic. This is a medicine that has already been approved by the FDA, and maybe in the future we will be able to give it as a preventive medicine for melanoma, and anyone can apply it to the skin, like applying sunscreen from the sun."

In addition to implications in the field of preventive medicine, the new research also has implications for the ability to diagnose melanoma. "You have to understand that this is a cancer that develops over many years," says Dr. Levy. "When the dermatologist orders a biopsy, he and the pathologist monitor the tumor, and based on the depth of penetration of the cancer cells decide whether it is a benign or malignant tumor. If the tumor is a millimeter or two deep within the dermis, the doctor orders radiation therapy. Here we offer another and much more accurate method: to sample the cells and check whether the Notch signal has been activated in the melanoma cells. That's how you can tell, in black and white, if it's a benign or metastatic tumor, and these days we've already started collaborating with the Wolfson and Sheba medical centers."