Marker Discovered Signaling Squamous Cell Skin Cancer About To Spread
By Deborah Borfitz
March 15, 2023 | Researchers in the inflammatory and neoplastic dermatological diseases research group at the Hospital del Mar Medical Research Institute in Barcelona have found that dyskerin (DKC1), a protein that provides stability to non-coding small nucleolar RNAs (snoRNAs), signals when cutaneous squamous cell carcinomas (cSCC) are preparing to metastasize by migrating to the lymph nodes. Because these cancer cells temporarily stop consuming glucose and instead feed on low-density lipoprotein (LDL) cholesterol molecules, the new marker may be a promising candidate for treatments involving lipid metabolism inhibitors, according to principal investigator Inmaculada Hernández-Muñoz, Ph.D.
As detailed in an article that recently published in Life Science Alliance (DOI: 10.26508/lsa.202201692), this mechanism is marked by the expression of enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) involved in cholesterol metabolism. “We found that cultured cells with low levels of DKC1 had, among other enzymes of the lipidic metabolism, high levels of HMGCS1... and had a high avidity for LDL, says Hernández-Muñoz. “In addition, these cells displayed a migratory phenotype.”
Initially, she explains, the research team found a decline in snoRNA expression in primary cSCC that subsequently metastasized to lymph nodes. They then saw that “the number of primary tumors expressing DKC1 was lower in the case of primary tumors that... metastasized, although statistical significance was not reached possibly because of the limited size of the cohort. What we did observe was that the number of metastases expressing DKC1 was significantly lower than in primary tumors expressing DKC1.
“DKC1 depletion in cultured cSCC cells induced an increase in cholesterol metabolism, and reduced the glucose utilization pathway,” Hernández-Muñoz continues. “We have not determined the levels of glucose uptake, but the levels of glucose metabolites suggest that glucose consumption must be greatly reduced.”
With cell cultures, the migratory and invasive abilities of the cells with low DKC1 levels could be impaired using statins that inhibit the enzyme (HMGCR) that is immediately downstream of HMGCS1, she says. When looking at the expression of this enzyme in SCC samples, researchers observed that “HMGCS1 expression correlates with clinicopathological criteria for poor prognosis.” Further, 44% of metastases expressed this enzyme, which is “much higher than the percentage of primary tumors expressing it [20%].”
Hernández-Muñoz notes that cSCC is “one of the tumors with the highest number of genetic alterations, as its appearance is closely linked to exposure to the sun [ultraviolet rays].” It was therefore surprising that 100% of metastases would express HMGCS1. “High mutational load can make some of these tumors highly resistant to the adverse conditions involved in the metastatic process and they do not need to adapt to the environment of the lymph node.”
The idea that DKC1 and snoRNAs are involved in metastatic cSCC had not previously been hypothesized, says Hernández-Muñoz. “High levels of DKC1 have generally been correlated with poor prognosis in other solid tumor types, probably because of functions that favor cell proliferation in the primary tumor and in organs colonized by metastases.”
In terms of the involvement of lipid metabolism, other groups have shown that metastatic cells are dependent either on fats (e.g., palmitic acid in the case of head and neck SCCs) or fatty acid oxidation (e.g., melanoma), she adds. The early stages of metastasis have traditionally been explained in part by “hypoxia-induced molecular mechanisms... favored by a pro-tumor inflammatory environment.”
Only about 4% of all SCCs that originate in the skin metastasize, a much lower percentage than those generated by tumors in the head and neck, says Hernández-Muñoz. This may be because of the inherent properties of the cancer cells as well as the “extensive cross-talk between them and the non-transformed stroma.” In the skin, SCC emerges from “highly differentiated and keratinized cells notably refractory to changes in their phenotype.”
SCC aggressiveness appears to depend on the organ where the cancer forms, she says. Cells isolated from a primary cSCC and injected into the tongue of nude mice, for example, result in tumors with an invasive growth pattern. The same cells injected subcutaneously form non-invasive tumors.
Similarly, “tongue tumors result in lymph node metastases, but not skin tumors generated by the same cells, according to the correlation between lymphatic vessel density and the lymph node metastases found in many cancers,” continues. “These data indicate that cSCC invasiveness is highly dependent on the tumor microenvironment.”
Statins Might Help
So, what are the key takeaways here? While “it cannot be ruled out that people with elevated LDL cholesterol levels are at higher risk [of metastasis]... cholesterol is constitutively part of cell membranes... [and] tumor cells already have these fats in their environment, and even more so when they migrate to the vessels/lymph nodes, as these have a high fat content,” Hernández-Muñoz says.
“That said,” she adds, “it is always better from a health point of view to have LDL cholesterol within normal levels.” And statin drugs, which are designed to lower LDL cholesterol, are inhibitors of the HMGCR enzyme and therefore, “would be suitable to limit or minimize this particular step of metastasis.”
Results to date support the use of statins before the appearance of metastases in secondary organs, says Hernández-Muñoz, particularly since they are so widely prescribed. Still, epidemiological studies are needed to establish the relationship between the use of the drugs and the presence of metastases in patients with different types of SCCs to support their potential therapeutic utility.
Publicly available data indicate a correlation between low levels of DKC1 and poor prognosis in lung and ovarian cancer, Hernández-Muñoz notes, which suggests “a similar mechanism could account for tumor dissemination in these two types of tumors.” This mechanism of adaptation to lymph node survival will likely be used by most solid tumors that tend to spread via this route. The phenomenon is “restricted to a very short period of time,” she adds, so is not as easily detected as the growth of metastatic seeding in secondary organs.
Hernández-Muñoz and her colleagues are now developing an experimental in vivo model of lymph node metastasis that will enable them to evaluate different therapies with metabolic targets. They are also collaborating with clinical groups to investigate the role of DKC1 and cholesterol metabolism in other tumor types.