Location, Location, Location: Cell Position is Important for Melanoma Development

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Vicky Tan

Cancer severity and therapy responses can be influenced by both the cell of origin and its location. Melanoma is a skin cancer that arises from pigment-producing cells, called melanocytes. Melanoma is predicted to become the third most commonly diagnosed cancer in Australia, while in the US, 100,000 new cases were expected in 2021 (1, 2). 

Melanoma subtypes are dictated by their anatomical location and level of damage caused by chronic sun exposure. When people talk about skin cancer, they are often referring to the more common cutaneous melanoma, where cancerous melanocytes spread across the superficial layer of the skin. A much rarer subtype, acral melanoma can arise from under the nails, soles of the feet, or palms. Acral melanoma patients have a lower overall survival rate and response rate to existing therapies. 

Different melanoma subtypes are associated with varying genetic changes. Cutaneous melanomas are primarily characterized by single-nucleotide mutations in genes, with about 50% of cutaneous melanomas having BRAF mutations (3). Consequently, targeting BRAF mutations has been pivotal in treating cutaneous melanomas. On the contrary, acral melanoma patients rarely have this genetic mutation and are ineligible for BRAF therapies (4). Consequently, a better understanding of the genetic profile and how the anatomical position of tumor-initiating cells affects their tumor growth is required.

The lack of animal models to study acral melanoma has been a major hurdle to better understanding this disease. In their recent Nature study, Weiss et al. identified key oncogenic signaling proteins CRKL and GAB2 were enriched in acral melanoma patients (5). Furthermore, alterations in genes NF1 and TERT are known to co-occur with CRKL and GAB2 mutation. With this in mind, the group developed a transgenic zebrafish model of acral melanoma whereby melanocytes specifically express CRKL and GAB2, TERT but lack NF1. Zebrafish fins are a comparable location to human palms or soles, and in their model, they observed that almost 70% of the animals developed acral tumors in the fin. Interestingly, they observed that CRKL alterations alone were able to drive tumor formation. In finding this vulnerability of fin melanocytes to CRKL changes, they identified a novel genetic alteration that drives acral melanoma formation.  

Next, the group wanted to better understand why fin melanocytes with CRKL alterations were susceptible to cancer formation. They sequenced zebrafish body and fin melanocytes in wild-type and acral melanoma fish and identified distinct gene profiles between cells from the two anatomical locations. Fin melanocyte genes were enriched for pathways related to limb development, and in particular, there was an upregulation of the master regulator of limb development gene, HOX13. Importantly, this enrichment was also seen in human patient acral melanoma samples, demonstrating that what they saw in zebrafish is conserved in humans. 

Weiss et al. hypothesized that CRKL and HOX13 could potentially work together to drive acral melanoma in fins. They found that HOX13 binding sites were associated with the activation of IGF1 and IGF2, genes important for limb development and regeneration. As CRKL is known to regulate the IGF1-PI3K signaling pathway, the group blocked this pathway, both genetically and pharmacologically in their acral zebrafish mode and observed decreased tumor formation in the fin. 

The novel acral melanoma model developed by Weiss et al. has helped uncover key drivers of acral melanoma development that can be potential therapeutic targets. Their work demonstrated that melanocytes from different anatomical locations have distinct susceptibility to genetic changes, which ultimately influence their ability to promote tumor growth. These insights may help explain why in other cancer types, genetic alterations only affect some tumor cells in a given anatomical location. Ultimately, this could help clinicians in determining the most appropriate cancer treatment based on a tumor’s location. 

Edited by Ifeoluwa Oyelade

Work discussed

Weiss, J. M. et al. Anatomic position determines oncogenic specificity in melanoma. Nature (2022) doi:10.1038/s41586-022-04584-6 

References

1. https://www.canceraustralia.gov.au/cancer-types/melanoma/statistics 
2. Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer Statistics, 2021. CA Cancer J. Clin. 71, 7–33 (2021) 
3. Tanda, E. T. et al. Current state of target treatment in BRAF mutated melanoma. Front. Mol. Biosci. 7, 154 (2020)
4. Mao, L., Qi, Z., Zhang, L., Guo, J. & Si, L. Immunotherapy in acral and mucosal melanoma: Current status and future directions. Front. Immunol. 12, 680407 (2021)
5. Weiss, J. M. et al. Anatomic position determines oncogenic specificity in melanoma. Nature (2022) doi:10.1038/s41586-022-04584-6

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