Decoding Melanoma Development and Progression: Identification of Therapeutic Vulnerabilities

Abstract

Melanoma, a cancer of the skin, arises from transformed melanocytes. Melanoma has the highest mutational burden of any cancer partially attributed to UV induced DNA damage. Localized melanoma is "curable" by surgical resection and is followed by radiation therapy to eliminate any remaining cancer cells. Targeted therapies against components of the MAPK signaling cascade and immunotherapies which block immune checkpoints have shown remarkable clinical responses, however with the onset of resistance in most patients, and, disease relapse, these patients eventually become refractory to treatments. Although great advances have been made in our understanding of the metastatic process in cancers including melanoma, therapy failure suggests that much remains to be learned and understood about the multi-step process of tumor metastasis. In this review we provide an overview of melanocytic transformation into malignant melanoma and key molecular events that occur during this evolution. A better understanding of the complex processes entailing cancer cell dissemination will improve the mechanistic driven design of therapies that target specific steps involved in cancer metastasis to improve clinical response rates and overall survival in all cancer patients.

Keywords: melanoma; melanoma progression; melanoma therapies; metastasis; signaling pathways.

Figure 1

Factors Which Contribute to Melanocytic Transformation. Created with BioRender.com.

Figure 2

Exosomes. Melanoma exosomes create a pre-metastatic niche at distal sites to support melanoma cell dissemination. Created with BioRender.com.

Figure 3

Melanoma Metastasis. Three routes of primary melanoma dissemination are outlined. A primary melanoma can undergo 1) passive shedding of tumor cells, non-EMT (epithelial to mesenchymal transition) followed by passive intravasation, 2) tumor cells can undergo EMT and active intravasation or 3) melanoma cells can undergo EMT and bring along non-EMT tumor cells, where the EMT cells are actively intravasating while the non-EMT cell are undergoing passive intravasation. Once in circulation, tumor cells will migrate to site of metastasis. If the tumor cells are active, they will undergo the canonical extravasation by mesenchymal to epithelial transition (MET). If the tumor cells are dormant, they will transdifferentiate into endothelial cells at the intravascular niche, undergo endothelial to mesenchymal transition (EndMT) and extravasate into the niche. Created with BioRender.com.

Figure 4

Angiogenesis in Melanoma. A mechanism to provide nourishment to the growing tumor cells and establish routes to distant metastatic sites. Vascular Endothelial Growth Factor (VEGF), Fibroblast Growth Factor (FGF), Interleukin-8 (IL-8), and Placental Growth Factor (PlGF). Created with BioRender.com.