Pre-clinical modeling of cutaneous melanoma

Abstract

Metastatic melanoma is challenging to manage. Although targeted- and immune therapies have extended survival, most patients experience therapy resistance. The adaptability of melanoma cells in nutrient- and therapeutically-challenged environments distinguishes melanoma as an ideal model for investigating therapy resistance. In this review, we discuss the current available repertoire of melanoma models including two- and three-dimensional tissue cultures, organoids, genetically engineered mice and patient-derived xenograft. In particular, we highlight how each system recapitulates different features of melanoma adaptability and can be used to better understand melanoma development, progression and therapy resistance.

Fig. 1. The striking features of melanoma.

a Melanoma cells display high levels of mutational burden in cancer. b Melanoma cell signal transduction pathways contain significant redundancy in response to therapy, allowing for rapid signal rewiring to avoid cell death. c Invasive, stem-like, and proliferative cell states are distinct intra-tumoral phenotypes that drive melanoma aggressiveness. d Melanoma cells secrete factors akin to stromal cells, promoting melanoma cell viability in an autocrine manner. e Melanoma cells secrete factors that reprogram adjacent stroma which, in turn, secrete pro-tumorigenic factors that promote melanoma aggressiveness in a paracrine manner. f Melanoma cells can survive the harsh environment of systemic circulation, with >70% melanoma patients possessing brain metastases at autopsy. g Melanoma cells readily survive ex vivo, allowing for high success rate in establishing cell lines and PDX.

Fig. 2. Available melanoma models.

a A large number of in vitro models are available to investigate specific properties of melanoma cells, including proliferation, migration, invasion, metastasis, heterogeneity, plasticity, and microenvironment interactions. b In vivo models capable of investigating adaptive immune dynamics require murine melanoma models, whereas (c) models utilizing human melanoma tumor models lack functional adaptive human systems. Scientific illustration toolkits from Motifolio (www.motifolio.com) were used to generate this figure.

Fig. 3. Minimal residual disease epitomizes the clinical challenge of heterogeneity and tumor plasticity.

a A small subpopulation of melanoma cells possess stem-like molecular and biological properties and undergo cellular proliferation at a slower rate than the rest (b, c) of the population. d Upon the addition of therapy (Rx), the bulk of the tumor is eliminated, except the stem-like subpopulation (minimal residual disease). e Under continuous therapy, the stem-like cells continue to proliferation and have the capacity to birth non-stem-like progeny. f Upon termination of therapy, the stem-like cells will again become scarce as the “normal” cycling cells continue to proliferate at a higher extent.