Deciphering Tumour Heterogeneity: From Tissue to Liquid Biopsy

Abstract

Human solid malignancies harbour a heterogeneous set of cells with distinct genotypes and phenotypes. This heterogeneity is installed at multiple levels. A biological diversity is commonly observed between tumours from different patients (inter-tumour heterogeneity) and cannot be fully captured by the current consensus molecular classifications for specific cancers. To extend the complexity in cancer, there are substantial differences from cell to cell within an individual tumour (intra-tumour heterogeneity, ITH) and the features of cancer cells evolve in space and time. Currently, treatment-decision making usually relies on the molecular characteristics of a limited tumour tissue sample at the time of diagnosis or disease progression but does not take into account the complexity of the bulk tumours and their constant evolution over time. In this review, we explore the extent of tumour heterogeneity with an emphasis on ITH and report the mechanisms that promote and sustain this diversity in cancers. We summarise the clinical strikes of ITH in the management of patients with cancer. Finally, we discuss the current material and technological approaches that are relevant to adequately appreciate ITH.

Keywords: circulating tumour DNA; liquid biopsy; multi-region sampling; next-generation sequencing; single-cell approaches; treatment resistance; tumour heterogeneity.

Figure 1

A multifaceted heterogeneity in cancers. (A) Inter-tumour heterogeneity refers to the variability observed in tumours of the same histological subtypes between different patients. (B) Intra-tumour heterogeneity (ITH) is observed across different regions of the primary tumour site and/or metastatic sites (spatial ITH) and can evolve over time (temporal ITH). Colours represent the different characteristics between tumours or tumour cells.

Figure 2

Sources of intra-tumour heterogeneity (ITH). Genetic, epigenetic, microenvironmental, transcriptomic and proteomic heterogeneities coexist in tumours and are linked with phenotypic diversity. Abbreviations: CAF: Cancer-associated fibroblasts; ECM: extracellular matrix; EMT: epithelial-to-mesenchymal transition; indels: small insertions and deletions; LOH: loss of heterozygoty; MET: mesenchymal-to-epithelial transition; SCNA: somatic copy number alterations; SNV: single nucleotide variants; SV: structural variants.

Figure 3

Models of tumour evolution described by Muller plots, which represent the tumour clonal dynamics over time. Colours indicate the different genotypes of the tumour cell clones.

Figure 4

Emerging approaches to capture intra-tumour heterogeneity (ITH). (A) Single-cell approaches profile the characteristics of each cell individually. Compared to bulk-tumour sampling (B), multi-region sequencing (C) measures cellular heterogeneity in distinct regions of the primary site and of the metastases and/or tissue biopsy samples collected at different time points of the disease. (D) Representative sampling (Rep-Seq) implies the analysis of a mixed solution composed of tumour residual material that has not been used for standard pathologic procedures. (E) Liquid biopsy consists in the analysis of tumour-derived components shed in body fluids.