Single cell analysis to dissect molecular heterogeneity and disease evolution in metastatic melanoma

Abstract

Originally described as interpatient variability, tumour heterogeneity has now been demonstrated to occur intrapatiently, within the same lesion, or in different lesions of the same patient. Tumour heterogeneity involves both genetic and epigenetic changes. Intrapatient heterogeneity is responsible for generating subpopulations of cancer cells which undergo clonal evolution with time. Tumour heterogeneity develops also as a consequence of the selective pressure imposed by the immune system. It has been demonstrated that tumour heterogeneity and different spatiotemporal interactions between all the cellular compontents within the tumour microenvironment lead to cancer adaptation and to therapeutic pressure. In this context, the recent advent of single cell analysis approaches which are able to better study tumour heterogeneity from the genomic, transcriptomic and proteomic standpoint represent a major technological breakthrough. In this review, using metastatic melanoma as a prototypical example, we will focus on applying single cell analyses to the study of clonal trajectories which guide the evolution of drug resistance to targeted therapy.

Fig. 1. Schematic diagram illustrating single cell analysis ability to solve intratumor heterogeneity.

Bulk tumour is constituted by different cellular elements of malignant, stromal and immune origins whose molecular state is difficult to determine when considered all together. Furthermore, bulk tumours can also contain malignant cells with different trascriptomic programs which help them to metastatize or resist antineoplastic agents. Single cell approaches are emerging as valuable tools in dissecting those complexities from genomic, transcriptomic and proteomic perspectives and in potentially determining the molecular signatures of every cell and its destiny during the course of the disease

Fig. 2. Schematic diagram illustrating single cell analysis implementation with liquid biopsies to gain diagnostic purposes.

Bulk melanomas contain a little percentage of dormant drug resistant cells before starting MAPKi treatments, which emerge as a resistant population passing in a drug-tolerant phase during the course of the therapy. Non invasive liquid biopsies may help to longitudinally measure the evolution of the therapy in order to predict the emergence of drug resistance and potentially predispose new tools to counteract it

Fig. 3. Schematic representation illustrating the major advantages brought by single cell studies to melanoma research.

Single cell studies allow to learn several lessons about intratumour heterogeneity which drives melanoma progression as well as the impact of targeted/immuno-therapies through the characterization of the crosstalks with the cellular and non cellular elements of the tumour microenvironment