Investigation of body clock could point to target for treatment of skin cancer

Researchers provide evidence of possible new therapeutic targets for melanoma and enhanced treatment of vitiligo.

By José Tadeu Arantes  |  Agência FAPESP – Melanoma is one of the most aggressive types of cancer. It arises from a malignant transformation of pigment cells, causing them to respond abnormally to visible and ultraviolet light. A thematic research project hosted by the University of São Paulo’s Bioscience Institute (IB-USP) in Brazil has shown that such alterations are due to disturbances in both the light receptor system of these cells and their timekeeping system, or “clock.” Based on this study, it is possible to foresee that these two systems will become attractive targets for the treatment of melanoma.

The project in question is “Biological clock setting by light and temperature: phylogenetic aspects”. Its principal investigator is Ana Maria de Lauro Castrucci, a professor at IB-USP, and it is supported by FAPESP. The research is also being conducted under the aegis of two other projects supported by FAPESP via a direct doctorate scholarship awarded to Leonardo Vinicius Monteiro de Assis and a postdoctoral scholarship awarded to Maria Nathália Moraes.

Castrucci heads a laboratory that has always investigated the physiology of pigmentation, with a comparative focus (invertebrates, non-mammalian vertebrates, mammalian vertebrates and humans). She spent a sabbatical with the Uniformed Services University of the Health Sciences (USUHS), a health science university run by the US federal government, where a group was working with directly light-sensitive pigment cells from amphibian skin.

“I was with this group in Bethesda, Maryland, when we discovered that the photopigment found in amphibians is also present in the retina of mice,” Castrucci told Agência FAPESP. “Since then, I’ve included in my thematic projects the investigation of these opsins in the peripheral tissues of vertebrates, with the aim of understanding their responses to light, temperature and hormones.”

Non-visual responses to light are associated with the presence of a group of proteins called melanopsins. The name reflects the fact that they were discovered in the melanophores of amphibians and not in the retina, as with other opsins. Melanopsins take part in processes such as adjustment of the central biological clock. Located in the hypothalamus in mammals, this clock controls rhythmic functions that range from sleeping and eating to body temperature and the release of various hormones, such as cortisol.

Thanks to the presence of melanopsins, fish and amphibian skin cells are directly responsive to light. In amphibians, the response may be a migration of pigment granules inside pigment cells, leading to a change in skin color, such as darkening.

“In non-mammalian vertebrates, we showed that photons interact with melanopsins and trigger cell signaling as a cascade of events similar to that produced by light in a mammal’s retina. This is a pathway that has been conserved by evolution. Melanopsin is an ancient opsin in evolutionary terms. It’s more primitive in the sense that it doesn’t form images. It’s a photopigment that serves only in the perception of dark and light. The fact that the cascade induced by light in the skin of these non-mammals is identical to the cascade induced by light in the human retina is an important finding in comparative physiology,” Castrucci said.

“Our group at USP was the first to demonstrate that melanopsins are also present in the pigment cells of birds and mammals and that they may play a role in adjusting the clock of mammalian pigment cells in response to visible, infrared and ultraviolet light.”

Given that melanopsin is linked to the perception of light and the central biological clock, the researchers wondered whether these peripheral cells that respond to light might not also be clocks and, if so, how response to light regulated their timekeeping mechanism. They therefore set out to investigate the signaling pathways involved in the cascade of events triggered by the exposure of melanopsins to light.

“We refuted the paradigm that mammals can only perceive light via the retina. We showed that pigment cells called melanocytes can also respond to light by increasing melanin synthesis and modifying so-called clock genes,” Castrucci said. “This response is exacerbated in melanomas, which are malignant melanocytes. Given that melanomas are so light-sensitive and that their clock genes are so severely affected, we can think of the mechanisms involved as potential therapeutic targets against the progression of this type of cancer.”

Another finding of this project is that the responses induced by UV-A radiation, such as increased melanin content and clock gene activation, are lost when this stimulus is associated with heat. This is the first report of an interaction between UV-A and heat, and it could serve as a basis for treating patients with pigmentation disorders such as vitiligo.

In the specific case of melanoma, the research has so far been performed in vitro with cultured cells. The next step planned by the group is to investigate the process in vivo with mice, comparing the peripheral timekeeping mechanisms in animals with and without melanomas. “We’re starting this phase now,” Castrucci said. “We plan to study not only tumors and surrounding tissue but also other organs, as although cancer is known to have macro effects on several of these, including the liver, adipose tissue and brown adipose tissue, they aren’t well understood.”

This potential avenue for the prevention and treatment of cancer and pigmentation disorders promises vast applications for a large-scale line of research that is currently being conducted in the field of basic science.