Investigating intratumour heterogeneity by single-cell sequencing

Abstract

Intratumour heterogeneity is a longstanding field of focus for both researchers and clinicians. It refers to the diversity amongst cells within the same tumour. Two major hypotheses have attempted to explain the existence of intratumour heterogeneity: (i) the clonal evolution (CE) theory and (ii) the cancer stem cell (CSC) model. CE theory emphasizes the evolutionary biological characteristics of the tumour, underscoring the initiation and progression of the disease. In contrast, the CSC model focuses on stem cell differentiation into distinct functions in order to stabilize the tumour microenvironment. Here we consider single-cell sequencing (SCS) as a newly developed technique for application to the investigation of intratumour heterogeneity and assess its relevance within research and clinical environments. Early detection of rare tumour cells, monitoring of circulating tumour cells (CTCs) and control of the occurrence of drug resistance are important goals in early diagnosis, prognosis prediction and individualized medicine.

Figure 1

Intratumour heterogeneity through space and time. In a tumour, genetic and epigenetic alterations may result from the emergence of a group of self-renewing CSCs. Through microenvironment interventions, including the immune response and drug treatment, some CSCs are inhibited. However, some genetic alterations occur in specific CSCs, helping the CSC to gain the ability to survive treatment, a process that is known as clonal evolution. After several cycles of intervention, the surviving CTC is capable of tumour progression and metastasis, affecting the patient's survival. CSC, cancer stem cell; CTC, circulating tumour cell.

Figure 2

The application of SCS in clinics. (a) Profiling of rare tumour cells in a clinical sample, assisting in early diagnosis. (b) Isolation and profiling of CTCs for detection. (c) Identification and profiling of some drug resistant tumour cells for the purpose of individualized treatment. CTC, circulating tumour cell; SCS, single-cell sequencing.