Metastasizing and non-metastasizing thick melanomas: clinicopathological predictors and molecular profiling.

Cutaneous melanoma (CM) is the most aggressive form of skin cancer and accounts for 80% of all skin cancer mortality. While early-stage CM is generally curable with early detection and surgery, diagnosis at a late stage with consequential delay of the treatment has a relevant negative effect on survival. This is due to the propensity of CM to metastasize and to the resistance of metastatic cells to classical cytotoxic chemotherapy. Targeted therapies and immunological approaches for the treatment of metastatic disease have dramatically improved survival in CM. Nevertheless, these therapies are not effective in all patients, and are burdened by adverse effects and development of resistance. It has become crucial to identify prognostic and predictive biomarkers to assist in developing personalized therapy and follow-up care. The most powerful prognostic marker is Breslow thickness. The risk of metastasis increases proportionally with the thickness of the CM. Nevertheless, Breslow thickness fails to stratify the prognosis in two groups of patients: on one hand, the ones with high Breslow that do not metastasize and, on the other hand, the ones with low Breslow that do metastasize. Therefore, a significant knowledge gap remains regarding more specific clinicopathological predictors for outcome that can allow us to better stratify the prognosis for patients with thick CM. The clinical, pathological and molecular differences between thick non-metastasizing CMs and thick metastasizing CMs, that could help to explain the different clinical behavior, are not yet fully elucidated. Understanding these differences will increase the knowledge of the alterations that underpin critical clinical, molecular and immunological events that lead to metastasis, helping in finding new targets for drugs that could be used in secondary prevention, highlighting new potential prognostic and predictive biomarkers and ultimately improving patient care and prognosis. CM metastatization is a very complex process and may be better visualized as a network rather than a linear series. As there are many routes to primary tumor formation, there are also likely many routes to the establishment of clinically meaningful metastatic disease. The metastatization process itself in CM has not been fully understood yet. The underlying biology of thick CMs is still a challenge and, so far, metastatization (RNA expression and protein expression) and its determinant mechanisms in thick CM has not been investigated in the past with a "multi-omics" approach. To become metastatic, tumor cells must overcome barriers that prevent them from dissemination and distant growth. In particular, they have to acquire alterations that allow them to invade, extravasate, colonize and grow in new microenvironments . CM spreading is the result of histopathologic alterations and molecular alterations, characterized by the changes in expression of proteins able to favor tumor invasion and infiltration, such as, for example, the expression in the microenvironment of the vasoactive peptide Endothelin-1 or the expression of matrix metalloproteinase 9 (MMP-9) by the CM cells. Several signaling pathways have been identified as key regulators in CM progression, such as activation of Ras/MAPK signaling pathway through the mutant BRAF or NRAS genes or alterations of CCND1. Additionally frequently affected molecular pathways are the PI3K/ AKT/mTOR (i.e., PTEN loss of function), cell cycle regulators (i.e., CDKN2a, CDK4, CCND1), P53 (i.e., Tp53, MDM2), and epigenetic regulation (i.e., ARID2a) pathways (12). Although many studies have investigated the distinct features of the CM spreading, no effort has been made to clarify the metastatization of thick CMs from a global perspective, through a global sequencing of the transcriptome instead of focusing only on single pathways. Finally, after the introduction of immunotherapies in clinical practice, to understand the CM microenvironment has become a priority. The differences in the immune microenvironment between metastasizing and non-metastasizing thick CM has not been investigated yet, even though it could be a determining factor to explain the different biological behavior. Nevertheless, multiple cell types are involved in the immune response, and they can influence and be influenced by the microenvironment to polarize into different functional states, according to the need for an active immune response or for induction immune tolerance. Better understanding of the microenvironment of thick CMs, in particular focusing on neovascularization and neolymphangiogenesis, macrophage polarization and tumor infiltrating lymphocytes, will shed lights on the precise role of these elements in CM progression.

Jaar van publicatie:2022

Toegankelijkheid:Open