Scientific and clinical implications of genetic and cellular heterogeneity in uveal melanoma

Abstract

Here, we discuss the presence and roles of heterogeneity in the development of uveal melanoma. Both genetic and cellular heterogeneity are considered, as their presence became undeniable due to single cell approaches that have recently been used in uveal melanoma analysis. However, the presence of precursor clones and immune infiltrate in uveal melanoma have been described as being part of the tumour already decades ago. Since uveal melanoma grow in the corpus vitreous, they present a unique tumour model because every cell present in the tumour tissue is actually part of the tumour and possibly plays a role. For an effective treatment of uveal melanoma metastasis, it should be clear whether precursor clones and normal cells play an active role in progression and metastasis. We propagate analysis of bulk tissue that allows analysis of tumour heterogeneity in a clinical setting.

Keywords: Driver mutation; Heterogeneity; Immune infiltrate; Precursor lesion; Uveal melanoma.

Fig. 1

Schematic representation of tumour development. Starting with one primary mutation, which differentiates healthy cells (empty circle) from an early tumour lesion (blue circle), many subsequent mutations are possible. The parental mutation will be present in all daughter cells (blue), while sub-clones are characterised by additional mutations. Non-tumorigenic mutations (beige, green, brown and yellow) do not lead to increased tumour growth, while tumorigenic mutations (red, black and purple) lead to successful tumour development. There are multiple ways a tumour can be unsuccessful, but there are limited ways to be successful

Fig. 2

Anatomy of uveal melanoma. (Modified from the figure of Diana Marques for UM Cure 2020, has gotten the permission) [13]

Fig. 3

Gαq signalling in uveal melanoma is achieved by mutations in CYSLTR2. GNAQ/11 and PLCB4. (Modified from the figure in [20])

Fig. 4

Different models of tumour development and the consequential tumour composition. Each circle represents a pool of cells with identical genetic alterations. In a cancer stem cell model, a vast pool of mutated stem cells produces daughter cells carrying its progenitor’s mutations and mutations unique for that clone. Characteristic for this model is the presence of multiple coexisting clones in the tumour mass. In a stochastic model, cells follow a specific path of mutations leading to increasingly smaller fractions which carry all its progenitor’s mutations. Sub-clones carrying different sets of mutations are unlikely in this model and thereby this model best reflects what we observe in UM

Fig. 5

Composition of an average UM. The majority of cells are mutated cancer cells, while a smaller portion consists of non-mutated healthy cells. Since UM grows in the acellular corpus vitreous, all these cells are part of the tumour. (Percentages are hypothetical but representative as described in De Lange et al. [79])

Fig. 6

UM development where multiple processes within a UM occur simultaneously. UM progression coincides with macrophage activation while the consequential chemokine expression (CXCL10) of activated macrophages is correlated with an influx of lymphocytes