A Portrait of Intratumoral Genomic and Transcriptomic Heterogeneity at Single-Cell Level in Colorectal Cancer

Abstract

In the study of cancer, omics technologies are supporting the transition from traditional clinical approaches to precision medicine. Intra-tumoral heterogeneity (ITH) is detectable within a single tumor in which cancer cell subpopulations with different genome features coexist in a patient in different tumor areas or may evolve/differ over time. Colorectal carcinoma (CRC) is characterized by heterogeneous features involving genomic, epigenomic, and transcriptomic alterations. The study of ITH is a promising new frontier to lay the foundation towards successful CRC diagnosis and treatment. Genome and transcriptome sequencing together with editing technologies are revolutionizing biomedical research, representing the most promising tools for overcoming unmet clinical and research challenges. Rapid advances in both bulk and single-cell next-generation sequencing (NGS) are identifying primary and metastatic intratumoral genomic and transcriptional heterogeneity. They provide critical insight in the origin and spatiotemporal evolution of genomic clones responsible for early and late therapeutic resistance and relapse. Single-cell technologies can be used to define subpopulations within a known cell type by searching for differential gene expression within the cell population of interest and/or effectively isolating signal from rare cell populations that would not be detectable by other methods. Each single-cell sequencing analysis is driven by clustering of cells based on their differentially expressed genes. Genes that drive clustering can be used as unique markers for a specific cell population. In this review we analyzed, starting from published data, the possible achievement of a transition from clinical CRC research to precision medicine with an emphasis on new single-cell based techniques; at the same time, we focused on all approaches and issues related to this promising technology. This transition might enable noninvasive screening for early diagnosis, individualized prediction of therapeutic response, and discovery of additional novel drug targets.

Neighboring macrophage-induced alteration in the phenotype of colorectal cancer cells in the tumor budding area

“…ITH has been shown to consist of subpopulations of cancer cells with different phenotypes [ 16 ]. These phenotypes are characterized by differences in gene expression (including protein expression), proliferation, metastatic potential, immunogenicity, and morphology [ 28 ].…”

“…Subpopulations of cancer cells with different phenotypes has shown to assemble and exhibit intratumoral heterogeneity (ITH) [ 16 ], which plays important roles in a highly malignant phenotype, characterized by features including chemoresistance [ 17 ]. Because topoisomerase 1 (TOPO1) is the enzyme that corrects supercoiled DNA [ 18 , 19 ], irinotecan, an inhibitor of TOPO1, would be often used as a drug for treating advanced CRC [ 19 ].…”

Single-cell sequencing technology in colorectal cancer: a new technology to disclose the tumor heterogeneity and target precise treatment

“…While the impact of the TME on CRC can be fully investigated by obtaining information on cancer cell characteristics through SCS, it is also possible to identify relevant predictive markers for CRC prognosis and potential immunotherapeutic targets through SCS, thus improving patient prognosis and therapeutic effects. In addition, the use of SCS technology for drug development and for addressing the problem of chemotherapy resistance in some patients is now emerging ( 31 ). It is expected to be applied in precision medicine to develop and personalize cancer medical treatments, providing a more accurate diagnosis and the best-individualized treatment plan for cancer patients.…”

“…CRC is characterized by genomic instability, epigenetic abnormalities, and abnormal gene expression ( 31 ). This has led to high tumor heterogeneity in patients with CRC.…”

Therapeutic Landscapes in Colorectal Carcinoma

“…Genome and transcriptome sequencing, together with editing technologies, are transforming biomedical research, and represent the most encouraging tools for defeating unmet clinical and research challenges. Bulk and single-cell next-generation sequencing are recognizing genomic and transcriptional heterogeneity in primary and metastatic tumors [ 16 ].…”