The Genetic Basis of Dormancy and Awakening in Cutaneous Metastatic Melanoma

Abstract

Immune dysregulation, in combination with genetic and epigenetic alterations, induces an excessive proliferation of uncontrolled melanoma cells followed by dissemination of the tumor cells to distant sites, invading organs and creating metastasis. Although immunotherapy, checkpoint inhibitors and molecular targeted therapies have been developed as treatment options for advanced melanoma, there are specific mechanisms by which cancer cells can escape treatment. One of the main factors associated with reduced response to therapy is the ability of residual tumor cells to persist in a dormant state, without proliferation. This comprehensive review aimed at understanding the genetic basis of dormancy/awakening phenomenon in metastatic melanoma will help identify the possible therapeutical strategies that might eliminate melanoma circulating tumor cells (CTCs) or keep them in the dormant state forever, thereby repressing tumor relapse and metastatic spread.

Dormancy of cutaneous melanoma

“…Intermediate STAT3 activation with a MITF low phenotype is expected to keep melanoma cells in the dormant state [113]. Further dormancy maintaining genes and modulating factors in melanoma are reviewed by Janowska et al [114].…”

“…Second, sophisticated 3D human modular in vitro and in vivo tumor dormancy models are needed to evaluate the complex interplay of tumor cells with microenvironmental factors and immune cells. Third, it has to be evaluated in the respective models which of the two different treatment options are more promising: either one keeps tumor cells in a dormant state, which implies the need to carry out lifelong treatment or one activates dormant cells in order to improve the efficacy of antiproliferative therapies [65,114].…”

“…Dormant tumor cells hiding in niches must be better characterized in patient tissue samples by highly advanced technological platforms (single cell technologies, highly multiplexed microscopy, imaging, bioinformatic analyses and machine learning tools). Based on this knowledge the path is clear to perform clinical studies for test effective therapeutic strategies in patients with dormant cancers [46,114,213].…”

Current Status in Rechallenge of Immunotherapy

“…They found that patients who responded to rechallenge had a shorter treatment interval than those who did not (1.6 vs. 4.7 months), suggesting that the immunological memory from the initial treatments could last after the treatment ends. Additionally, when the immune response from the initial treatment is weakened, the originally established tumor dormancy may be broken which in turn loses the control of tumor growth, and rebuilding it might take substantial effort [129]. Therefore, the researchers recommended rechallenging within 3 months.…”

Impact of anesthesia choice in cutaneous melanoma surgery

“…In experimental models, data has existed for several decades demonstrating that different forms of anesthesia have differential effects on immune system function, which in turn could influence tumor behavior [24,25]. Cancers, including melanoma, have the capacity to enter a dormant state, in which they exist in a steady state between growth and regression [26,27]. This concept, known as tumor dormancy, is believed to arise from an immunologic equilibrium between the host and the tumor [28,29].…”