2023 Project 6

Student Projects 2023: 1 Patterning neural border and NC | 2 NPB NEUcrest | 3 EMT and NC | 4 miRNA and NC | 5 Adrenal Gland and NC | 6 Melanocyte & Melanoma | 7 Neurocristopathies | Neural Crest These projects are the sole work of undergraduate science students and may contain errors in fact or descriptions.

Melanocytes & Melanoma

Melanocytes are pigment-producing cells derived from trunk neural crest cells (NCC). They are commonly known to be responsible for the pigmentation of our skin, iris, hair and body hair. The migration pathways of NCC that will allow melanoblasts, the melanocytes precursors, to reach their final locations are divided into two main routes: the dorsolateral and the ventral pathways (Figure1).

Figure 1: Schematic representation of melanoblast migration. Adapted from Y. Tang et al. 2020 1. The dorsolateral pathway is between the overlying ectoderm and the somites, while the ventral pathway is between the inner surface of the somite and the adjacent neural tube. Melanoblasts mostly migrate through the dorsolateral pathway and then colonize the epidermis. NCCs migrating via the ventral pathway are mostly neurogenic glial cells which will give rise to Schwann cells (glial-origin cells that surround the axons of neurons)2. Melanocytes can also originate from Schwann cell precursors, thus allowing different routes and time-wise delivery of these pigmentation cells to distant parts of the embryo 3.

Melanocyte and/or melanocyte derived cells also populate lesser-conventional locations in the body, where the production of pigment or protection against UV light is not at the core of its function. They can be found in the inner ear, as intermediate cells of the stria vascularis, in parts of the brains such as the substantia nigra and locus coeruleus, and also on the arachnoid and pia mater. In the eyes, clearly in the iris but also at the retina pigmented epithelia. At the cardiovascular system, these pigment producing cells can be found in cardiac valves, septum and arteries and veins of the heart 4.

An example of the aforementioned different routes of melanocytes colonization during embryogenesis can be seen in the inner ear. There, melanocytes of the cochlea come from Schwann cell precursors, while the melanocytes of the vestibule are derived from cells going through the ventral route 5.

Of the variously derived melanocytes, cutaneous ones are the most numerous. They are located at the base of the epidermis and are responsible for producing melanin pigments. Melanogenesis is the process in which eumelanin and pheomelanin are synthesised within lysosome-related organelles called melanosomes 6. These melanosomes mature through four stages. Immature (stages I and II) early melanosomes are lacking pigments and are located at the centre of the cell. Whereas premature and mature (stages III and IV) melanosomes are dark pigmented and traffic within the cell, towards the dendrites 7 to the upper keratinocytes to protect their nuclei from UV radiations 8 (Figure2).

Figure 2 : Schematic view of the melanosome maturation stages with electron microscopy examples (left) and their transport from melanocyte to upper keratinocytes (right). Adapted from Marks, M., Seabra, M. The melanosome: membrane dynamics in black and white. Nat Rev Mol Cell Biol 2, 738–748 (2001). https://doi.org/10.1038/35096009

Deregulation of these pigmented cells leads to the development of malignant melanoma. It is a very aggressive and treatment-resistant human skin cancer, responsible for approximately 80% of skin cancer mortality 9. Risk factors are multiple, including genetic inheritance, number and typicity of nevi, sun sensitivity, UV radiation and previous melanoma 9 10. Moreover it is characterised by a high mutational burden such that many mutations occur within the cancerous cells 11. The first stage of melanoma, “in situ”, is a radial and localised growth from the basal epidermis toward the surface of the skin. Later on, melanoma invades the dermis and reaches the hypodermis and so comes into contact with the vasculature and lymphatic systems 12 (Figure3), allowing the spreading of cells and material through an epithelial to mesenchymal like process (EMT-like process), also called phenotypic switching 13, when referred to melanoma. This event allows the acquisition of a more migratory and invasive phenotype that supports melanoma dissemination.

Figure 3 : Schematic view of the stages in malignant melanoma evolution process. Adapted from J. Jaworek-Korjakowska & P. Kleczek, 2018 14. Melanoma cells can keep certain features of their cellular origin, including melanosome production and trafficking 15 16. Melanoma melanosomes have a role in promoting melanoma tumorigenesis through the formation of the dermal tumour niche, before invasion 17. These particular aspects highlight the very nature of the melanosome as a cargo lysosome, able to carry, not only the pigment, but also specific markers of melanocyte/melanoma signature. This includes a wide variety of factors such as proteins and enzymes (TYR, TRP1, TRP2, MART1, PMEL17/GP100) but also smaller peptides, lipids, glycans and miRNA 18 19. These melanocyte/melanoma specific proteins can be processed as tumour-specific immunogenic epitopes, which may serve as important determinants in the adaptive immune response to cancer and are potentially important targets for immunotherapy. As previously mentioned, melanoma has a high mutational burden 11. Melanoma initiation happens due to the deregulation of specific signalling pathways, induced by mutations in key genes. The mitogen-activated protein kinase (MAPK) signalling cascade is the most affected, due to mutations in the BRAF, NF1 and/or NRAS genes 20. In the progression of the disease, additional genetic modifications characterise the melanoma mutational landscape, among them there are mutations in the TERT promoter and heterozygous genetic lesions in the CDKN2A locus 21, followed by mutations in the tumour suppressor genes TP53 and PTEN 11. However, melanoma progression toward a metastatic disease is not only supported by genetic modifications, but mostly by intra-tumoral heterogeneity and cancer cell plasticity. Indeed, inside the same cancer mass, melanoma cells can present different levels of proliferative and invasive capacities 22. Recently both melanoma development and progression have been associated with the re-emergence of a neural-crest stem cell-like state 23 24 25. Among the neural crest markers associated with melanoma there are Sox10 26 27 and CD271 28 24 29. Given the fact that melanocytes are neural-crest derived cells it is not surprising the reactivation of embryonic programs in melanoma. In the near future, cancer research must take advantage of this evidence to develop innovative target therapies.

References

1. Tang, Y., Durand, S., Dalle, S. & Caramel, J. EMT-Inducing Transcription Factors, Drivers of Melanoma Phenotype Switching, and Resistance to Treatment. Cancers (Basel). 12, 1–17 (2020). 2. Vandamme, N. & Berx, G. From neural crest cells to melanocytes: cellular plasticity during development and beyond. Cell. Mol. Life Sci. 76, 1919–1934 (2019). 3. Adameyko, I. et al. Schwann cell precursors from nerve innervation are a cellular origin of melanocytes in skin. Cell 139, 366–379 (2009). 4. Kaucka, M. et al. Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges. Cell. Mol. Life Sci. 78, 6033–6049 (2021). 5. Bonnamour, G., Soret, R. & Pilon, N. Dhh-expressing Schwann cell precursors contribute to skin and cochlear melanocytes, but not to vestibular melanocytes. Pigment Cell Melanoma Res. 34, 648–654 (2021). 6. Orlow, S. J. Melanosomes Are Specialized Members of the Lysosomal Lineage of Organelles. J. Invest. Dermatol. 105, 3–7 (1995). 7. Raposo, G. & Marks, M. S. Melanosomes — dark organelles enlighten endosomal membrane transport. Nat. Rev. Mol. Cell Biol. 2007 810 8, 786–797 (2007). 8. Cichorek, M., Wachulska, M., Stasiewicz, A. & Tymińska, A. Skin melanocytes: biology and development. Adv. Dermatology Allergol. Dermatologii i Alergol. 30, 30–41 (2013). 9. Arlo J Miller & Martin C Mihm Jr. Melanoma. N. Engl. J. Med. 355, 129–135 (2006). 10. Markovic, S. N. et al. Malignant Melanoma in the 21st Century, Part 1: Epidemiology, Risk Factors, Screening, Prevention, and Diagnosis. Mayo Clin. Proc. 82, 364–380 (2007). 11. Hodis, E. et al. A landscape of driver mutations in melanoma. Cell 150, 251–263 (2012). 12. Balch, C. M. et al. Final version of 2009 AJCC melanoma staging and classification. J. Clin. Oncol. 27, 6199–6206 (2009). 13. Pedri, D., Karras, P., Landeloos, E., Marine, J. C. & Rambow, F. Epithelial-to-mesenchymal-like transition events in melanoma. FEBS J. 289, 1352–1368 (2022). 14. Jaworek-Korjakowska, J. & Kleczek, P. ESkin: Study on the smartphone application for early detection of malignant melanoma. Wirel. Commun. Mob. Comput. 2018, (2018). 15. Borovansky, J., Mirejovsky, P. & Riley, P. A. Possible relationship between abnormal melanosome structure and cytotoxic phenomena in malignant melanoma. Neoplasma 38, 393–400 (1991). 16. Lazova, R. & Pawelek, J. M. Why do melanomas get so dark? Exp. Dermatol. 18, 934–938 (2009). 17. Dror, S. et al. Melanoma miRNA trafficking controls tumour primary niche formation. Nat. Cell Biol. 2016 189 18, 1006–1017 (2016). 18. Singh, S. K. et al. The silver locus product (Silv/gp100/Pmel17) as a new tool for the analysis of melanosome transfer in human melanocyte-keratinocyte co-culture. Exp. Dermatol. 17, 418–426 (2008). 19. Kawakami, Y. et al. The use of melanosomal proteins in the immunotherapy of melanoma. J. Immunother. 21, 237–246 (1998). 20. Shain, A. H. & Bastian, B. C. From melanocytes to melanomas. Nat. Rev. Cancer 16, 345–358 (2016). 21. Shain, A. H. et al. The Genetic Evolution of Melanoma from Precursor Lesions. N. Engl. J. Med. 373, 1926–1936 (2015). 22. Rambow, F., Marine, J. C. & Goding, C. R. Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities. Genes Dev. 33, 1295–1318 (2019). 23. White, R. M. et al. DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature 471, 518–522 (2011). 24. Diener, J. & Sommer, L. Reemergence of neural crest stem cell-like states in melanoma during disease progression and treatment. Stem Cells Transl. Med. 10, 522–533 (2021). 25. Huang, F., Santinon, F., Flores González, R. E. & del Rincón, S. V. Melanoma plasticity: promoter of metastasis and resistance to therapy. Front. Oncol. 11, (2021). 26. Rosenbaum, S. R. et al. SOX10 requirement for melanoma tumor growth is due, in part, to immune-mediated effects. Cell Rep. 37, 110085. (2021). 27. Abou-Hamad, J. et al. CEACAM1 is a direct SOX10 target and inhibits melanoma immune infiltration and stemness. iScience 25, 105524 (2022). 28. Boiko, A. D. et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 466, 133–137 (2010). 29. Ngo, M. et al. Antibody Therapy Targeting CD47 and CD271 Effectively Suppresses Melanoma Metastasis in Patient-Derived Xenografts. Cell Rep. 16, 1701–1716 (2016).