Moffitt Researchers Identify ‘Goliath’ Cell Groups That Could Help Explain How Skin Cancer Begins

Key Highlights 

• Moffitt researchers tracked more than 25,000 groups of related skin cells in mice to see how skin cancer developed over time. 

• After being exposed to ultraviolet radiation, some groups of these cells, called goliath clades, grew extremely large before acquiring established cancer-driving mutations. 

• Two of 21 goliath clades gave rise to visible skin lesions, suggesting that large groups of cells could be more likely than ordinary cell groups to lead to cancer. 

• The findings could help researchers identify early changes that make tissue vulnerable to cancer as well as help shape new approaches for preventing skin cancer. 

TAMPA, Fla. – Cancer is often believed to begin when cells accumulate genetic mutations that allow them to grow uncontrollably. However, human skin regularly accumulates an enormous number of age- and sun-related mutations associated with cancer, yet only a few ever go on to form a tumor. 

Findings from a new study by researchers at Moffitt Cancer Center may help explain why.  

The team, led by co-senior authors Kenneth Tsai, M.D., Ph.D., co-director of Moffitt’s Donald A. Adam Melanoma and Skin Cancer Center of Excellence, and Joel Brown, Ph.D., senior member of the Integrated Mathematical Oncology Department, hypothesized that there could be more to the story than just genetic changes. 

The study, published in Cancer Research, reveals an additional process involving changes in how cells are organized and behave, which may contribute to the earliest stages of cancer development. 

To observe cancer formation as it played out, the team used a hairless mouse model whose skin cells were treated to glow with unique fluorescent colors. This allowed the researchers to visually track the growth of specific cell families, known as clades. The researchers then exposed the mice to ultraviolet radiation, a major risk factor for cutaneous squamous cell carcinoma.  

Over several months, the scientists used high-contrast, 3D microscopy to monitor more than 25,000 fluorescently labeled clades, including clades from UV-exposed and unexposed skin. Most clades remain small, averaging about eight to 16 cells. UV exposure was associated with the emergence of a small number of exceptionally large cell groups, which the researchers called goliath clades. These large clusters typically contained more than 500 cells and often took on irregular shapes.  

Possible Addition to Current Model 

In a key finding, the researchers found that goliath clades formed before cells acquired established cancer-driving mutations. So, rather than mutations generating fast-expanding cell groups as the sole explanation, as the current model imagines, ultra-large clades may sometimes arise first — a second possible scenario for cancer formation. Because maintaining the supersized clades requires many rounds of cell division, they present more opportunities for mutations to accumulate subsequent to their formation. 

Next, the researchers closely followed 21 goliath clades in skin that appeared normal. Two eventually developed into visible lesions. The researchers calculated that the likelihood of finding two or more lesions among 21 randomly selected clades was less than one in a million. They caution, however, that the number of goliaths studied was too small to say precisely how often individual goliath clusters give rise to cancer. 

The Intriguing Presence of “Micro-Lumps” 

Further analysis showed that some goliaths contained tightly packed clusters of cells the authors call micro-lumps. Most clades exhibited no micro-lumps, and many only had one. Goliaths with more micro-lumps usually had higher numbers of genetic mutations. The likelihood that a clade had one or more micro-lumps increased with clade size, with goliaths exposed to UV light having the highest probability. The number of clades exposed to UV with four or more micro-lumps was 42, which was 10  times the number of those exposed to non-UV. The findings could encourage further research into whether the cells comprising the micro-lumps are nascent but otherwise undetectable cancer cells.  

Other Changes 

The researchers also found a higher proportion of actively dividing skin cells after UV exposure as well as changes in pathways that cells use to grow and produce energy (metabolism). Specifically, activity in the p53 pathway increased after UV exposure. p53 is a protein that helps cells detect and respond to DNA damage, for example, by slowing the division of damaged cells.  

Interferon signaling also increased. Interferons are proteins that help cells respond to infection and other threats as well as coordinate immune activity. The researchers also found more regulatory T cells, which are immune cells that help keep immune responses from becoming excessive. There were also more plasmacytoid dendritic cells, or immune cells that can produce large amounts of interferons.  

This pattern of changes may indicate that UV exposure does more than damage the DNA of skin cells. It could also change how cells grow, respond to damage and interact with the immune system. The result could be an environment where tissue-based alterations and genetic mutations act together during cancer development. 

If something similar happens in human skin, new strategies for cancer prevention could result, though considerable research is needed before new approaches could reach patients. 

Q&A With Co-Senior Authors Drs. Kenneth Y. Tsai and Joel S. Brown 

You found that unusually large goliath clades can form before established cancer-driving mutations appear. What does this say about the earliest stage of skin cancer development, and how could it change the standard mutation-first view of cancer? 

Our model of carcinogenesis has ecological and evolutionary components. Long runs of cell division (ecology) need to occur before a cell or group of cells can accumulate the necessary alignment of cancer-initiating changes and mutations. We propose that skin damage from UV results in goliaths as a normal skin healing process that maintains homeostasis. The ecological stage is now set for the evolutionary trajectory toward cancer. As an unintended consequence, these goliaths undergo many more cell divisions to maintain themselves, thus becoming incubators of cancer. 

Why might some groups of cells become goliaths after UV exposure while most remain small?  

We see the goliaths as cells pitching in to quickly resolve skin damage from UV radiation, like helping a neighbor shovel their sidewalk if they are unable to. Ironically, the good neighborly behavior of healing damaged skin leads to goliaths that only later accumulate mutations as a result of continuous cell divisions. Epidermis turns over about every 40 days. UV is the perfect carcinogen, where the consequences of skin healing may precede that of mutations on the road to cancer. 

If other researchers replicate your findings, what could that mean for the future of skin cancer prevention? 

There are three major consequences of rare goliaths spawning most skin cancers. First, we need not fear the goings-on of ordinary clades. Second, by focusing attention on the source and progression of goliath clades, we narrow the scope of cancer prevention. Third, creams containing agents that target goliath clades or reduce their occurrence following intense UV-exposure become viable cancer prevention agents. 

Might this same biology apply to other malignancies as well? 

Yes, but first, we have to establish whether the goliath framework is unique to UV or also applies in other cases where tissues become inflamed and might produce goliaths, for example, smoking or Crohn’s disease. In addition to the skin, sites where goliaths could form include other epithelial tissues, such as the lung, oropharynx and gastrointestinal tract. And perhaps beyond. 

This work was supported by the Melanoma & Skin Cancer Centers of Excellence, the Evolutionary Therapy Center of Excellence and the Molecular Genomics, Tissue Core, Analytical Microscopy, and Quantitative Imaging cores at Moffitt Cancer Center(P30-CA076292), and NIH NCI 5R01CA258089.  

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