Melanoma, a relatively rare but deadly skin cancer, has been shown to switch differentiation states — that is, to regress to an earlier stage of development — which can lead it to become resistant to treatment. Now, UCLA researchers have found that melanomas can be divided into four distinct subtypes according to their stages of differentiation. Cell subtypes that de-differentiated — meaning that they reverted back to a less-mature cell — showed sensitivity to a type of self-inflicted cell death called ferroptosis.
The research also showed that certain subtypes of melanoma cells could be successfully treated using multiple cancer therapies in combination with ferroptosis-inducing drugs.
Melanoma arises from melanocytes, cells that produce pigments. Although targeted therapies and a greater understanding of cancer immunology have significantly improved survival, many patients either relapse or do not respond to treatment.
The UCLA team, led by Dr. Thomas Graeber, analyzed the gene expression of melanoma cells and compared them to information in public genetic databases to identify the four different subtypes of melanoma with different drug sensitivities. The team organized the melanoma cells according to characteristic patterns of genes turned on by the cells. Comparing the gene expression patterns to data from stem cells induced to differentiate into melanocytes, they found that melanomas can be categorized into four distinct differentiation states.
“This refined characterization improves our understanding of the progressive changes that occur in melanoma cells during dedifferentiation, which can help develop better strategies to target this form of therapy resistance,” said Jennifer Tsoi, who was a member of the research team as a UCLA graduate student and now is a postdoctoral fellow at UCLA.
The investigators then searched pharmacogenomics databases for compounds that could best be used to treat melanomas characterized by the dedifferentiation expression pattern, either individually or in combination with other drugs.
The study introduces a new area of therapeutic possibilities for melanoma, because it is the first to link ferroptosis to melanoma differentiation states. It also more precisely defines different subtypes of melanoma, based on specific gene expression and metabolic profiles. Those subtypes characterize four steps along a trajectory taken by melanoma cells as they respond to exogenous stresses, such as drug treatments.
The approach for targeting dedifferentiated melanomas could complement existing standard-of-care therapies, since kinase inhibitors and immunotherapies are much more effective against differentiated cells than de-differentiated cells.
“Furthermore, these standard-of-care therapies can induce dedifferentiation, and thus in a co-treatment setting, ferroptosis induction can potentially block melanoma cells attempting to take this escape route,” Graeber said.
Eczema: A New Natural Brake On The Allergic Attack
Eczema affects about 17 percent of children in developed countries and is often the gateway to food allergy and asthma, initiating an “atopic march” toward broader allergic sensitization. There are treatments — steroid creams and a recently approved biologic — but they are expensive or have side effects. A new study in Science Immunology suggests a different approach to eczema, one that stimulates a natural brake on the allergic attack.
The skin inflammation of eczema is known to be driven by “type 2” immune responses. These are led by activated T helper 2 (TH2) cells and type 2 innate lymphoid cells (ILC2s), together known as effector cells. Another group of T cells, known as regulatory T cells or Tregs, are known to temper type 2 responses, thereby suppressing the allergic response.
Yet, if you examine an eczema lesion, the numbers of Tregs are unchanged. Interestingly, Tregs comprise only about 5 percent of the body’s T cells, but up to 50 percent of T cells in the skin.
“Our question was, is there something special about the Tregs that reside in the skin?” says Raif Geha, MD, chief of the Division of Immunology at Boston Children’s Hospital and the senior author of the study.
Geha led an investigation using two separate mouse models of eczema, each recreating a separate pathway leading to allergic skin inflammation. The team purified Tregs from the animals’ skin and blood and compared the genes they express.
Several genes were especially likely to be turned on in the skin Tregs. One encodes retinoid-related orphan receptor alpha (RORα), a transcription factor that itself regulates multiple other genes.
“We then used a genetic trick to remove RORα only from Tregs,” says Geha. “Without RORα, allergic inflammation went crazy in both our mouse models.”
The team saw a three-fold increase in the influx of inflammatory cells, and ILC2s and TH2 cells were at the center of the action.
Restraining allergic skin inflammation
Why did the Tregs stop working when RORα was removed? Geha and colleagues discovered that the cells made less of a receptor for a cytokine called TNF ligand-related molecule 1, or TL1A. TL1A is released by skin cells known as keratinocytes, and activates not only Tregs but also ILC2 and TH2 effector cells.
“The two kinds of immune cells are competing for TL1A,” Geha explains. “If Tregs don’t have this receptor, they can’t ‘see’ TL1A. Not only are they not activated, but more TL1A is available to activate the effector cells. So you have a double whammy.”
Testing human samples, the team documented higher expression of RORα in skin Tregs compared with those in blood, similar to mice.
Geha now wants to see if RORα is expressed less in human eczema and whether it’s important in the atopic march. If so, he sees several possible treatment approaches.
One is to boost RORα’s level or activity with compounds that act as RORα agonists, perhaps given in a topical cream. Geha’s lab also plans to look for factors in the skin that drive RORα activity, which could present other targets for intervention. Finally, the study showed that RORα regulates the expression of several genes important for Treg cell migration and function; those pathways could be potential targets too.
Study Shows Some Skin Bacteria May Protect Against Cancer
Science continues to peel away layers of the skin microbiome to reveal its protective properties. In a study published in Science Advances on February 28, University of California San Diego School of Medicine researchers report a potential new role for some bacteria on the skin: protecting against cancer.
“We have identified a strain of Staphylococcus epidermidis, common on healthy human skin, that exerts a selective ability to inhibit the growth of some cancers,” said Richard Gallo, MD, PhD, Distinguished Professor and chair of the Department of Dermatology at UC San Diego School of Medicine.
“This unique strain of skin bacteria produces a chemical that kills several types of cancer cells but does not appear to be toxic to normal cells.”
The team discovered the S. epidermidis strain produces the chemical compound 6-N-hydroxyaminopurine (6-HAP). Mice with S. epidermidis on their skin that did not make 6-HAP had many skin tumors after being exposed to cancer-causing ultraviolet rays (UV), but mice with the S. epidermidis strain producing 6-HAP did not.
6-HAP is a molecule that impairs the creation of DNA, known as DNA synthesis, and prevents the spread of transformed tumor cells as well as the potential to suppress development of UV-induced skin tumors.
Mice that received intravenous injections of 6-HAP every 48 hours over a two-week period experienced no apparent toxic effects, but when transplanted with melanoma cells, their tumor size was suppressed by more than 50 percent compared to controls.
“There is increasing evidence that the skin microbiome is an important element of human health. In fact, we previously reported that some bacteria on our skin produce antimicrobial peptides that defend against pathogenic bacteria such as, Staph aureus,” said Gallo.
In the case of S. epidermidis, it appears to also be adding a layer of protection against some forms of cancer, said Gallo. Further studies are needed to understand how 6-HAP is produced, if it can be used for prevention of cancer or if loss of 6-HAP increases cancer risk, said Gallo.
More than 1 million cases of skin cancer are diagnosed in the United States each year. More than 95 percent of these are non-melanoma skin cancer, which is typically caused by overexposure to the sun’s UV rays. Melanoma is the most serious form of skin cancer that starts in the pigment-producing skin cells, called melanocytes.
Our Facial Features Determined by Fifteen New Genes
Researchers from KU Leuven and the universities of Pittsburgh, Stanford, and Penn State (US) have identified fifteen genes that determine our facial features. The findings were published in Nature Genetics.
Our DNA determines what we look like, including our facial features. That appeals to the popular imagination, as the potential applications are obvious. Doctors could use DNA for a skull and facial reconstructive surgery, forensic examiners could sketch a perpetrator’s face on the basis of DNA retrieved from a crime scene, and historians would be able to reconstruct facial features using DNA from days long gone.
But first, researchers need to figure out which genes in our DNA are responsible for specific characteristics of our face.
“We’re basically looking for needles in a haystack,” says Seth Weinberg (Pittsburgh).
“In the past, scientists selected specific features, including the distance between the eyes or the width of the mouth. They would then look for a connection between this feature and many genes. This has already led to the identification of a number of genes but, of course, the results are limited because only a small set of features are selected and tested.”
Seven of the identified genes are linked to the nose, and that’s good news for forensic scientists.
In a new study conducted by KU Leuven in collaboration with the universities of Pittsburgh, Stanford and Penn State, the researchers adopted a different approach.
“Our search doesn’t focus on specific traits,” lead author Peter Claes (KU Leuven) explains.
“My colleagues from Pittsburgh and Penn State each provided a database with 3D images of faces and the corresponding DNA of these people. Each face was automatically subdivided into smaller modules. Next, we examined whether any locations in the DNA matched these modules. This modular division technique made it possible for the first time to check for an unprecedented number of facial features.”
The scientists were able to identify fifteen locations in our DNA. The Stanford team found out that genomic loci linked to these modular facial features are active when our face develops in the womb.
“Furthermore, we also discovered that different genetic variants identified in the study are associated with regions of the genome that influence when, where and how much genes are expressed,” says Joanna Wysocka (Stanford).
Seven of the fifteen identified genes are linked to the nose, and that’s good news, Peter Claes (KU Leuven) continues.
“A skull doesn’t contain any traces of the nose, which only consists of soft tissue and cartilage. Therefore, when forensic scientists want to reconstruct a face on the basis of a skull, the nose is the main obstacle. If the skull also yields DNA, it would become much easier in the future to determine the shape of the nose.”
With the same novel technology used in this study, we can also link other medical images – such as brain scans – to genes.
In any case, the four universities will continue their research using even bigger databases.
But we must not get ahead of ourselves, says Mark Shriver (Penn State):
“We won’t be able to predict a correct and complete face on the basis of DNA tomorrow. We’re not even close to knowing all the genes that give shape to our face. Furthermore, our age, environment, and lifestyle have an impact on what our face looks like as well.”
Peter Claes (KU Leuven), who specialises in computational image analysis, points out that there are other potential applications as well:
“With the same novel technology used in this study, we can also link other medical images – such as brain scans – to genes. In the long term, this could provide genetic insight into the shape and functioning of our brain, as well as in neurodegenerative diseases such as Alzheimer’s.”
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