Understanding cell-cell communication and signaling in the colorectal cancer microenvironment

Abstract

Carcinomas are complex heterocellular systems containing epithelial cancer cells, stromal fibroblasts, and multiple immune cell-types. Cell-cell communication between these tumor microenvironments (TME) and cells drives cancer progression and influences response to existing therapies. In order to provide better treatments for patients, we must understand how various cell-types collaborate within the TME to drive cancer and consider the multiple signals present between and within different cancer types. To investigate how tissues function, we need a model to measure both how signals are transferred between cells and how that information is processed within cells. The interplay of collaboration between different cell-types requires cell-cell communication. This article aims to review the current in vitro and in vivo mono-cellular and multi-cellular cultures models of colorectal cancer (CRC), and to explore how they can be used for single-cell multi-omics approaches for isolating multiple types of molecules from a single-cell required for cell-cell communication to distinguish cancer cells from normal cells. Integrating the existing single-cell signaling measurements and models, and through understanding the cell identity and how different cell types communicate, will help predict drug sensitivities in tumor cells and between- and within-patients responses.

Keywords: CITE-seq; CellPhoneDB; Colorectal cancer (CRC); CyTOF; Tumor microenvironments (TME); patient-derived explant (PDE); patient-derived organoid (PDO); patient-derived xenografts (PDX); scRNA-seq.

FIGURE 1

(A) Schematic representation of multiple cell‐cell communication in the colonic epithelium and colon adenocarcinoma. The arrows represent activated interactions between heterotypic cells. Left) “Normal” heterotypic cell‐cell interactions that maintain homeostasis and functionality of colonic epithelium. Right) The emergence of malignant phenotypes by oncogenic mutations, influenced by increased cell‐cell communication by different signaling pathways that were not activated before as well as the recruitment of more cell types. (B) Cellular heterogeneity maintained in a patient‐derived explant platform. In the patient‐derived explant system, the tumor samples are directly obtained from patients’ tissues following surgery as compared to other in vitro and in vivo approaches previously mentioned. Patient‐derived explant system provides an accessible model to study multiple cell‐cell communication interactions, and offer a promising platform for precision medicine approaches.

FIGURE 2

Histological examination of a colorectal cancer‐patient‐derived explant model. Hematoxylin and eosin (H&E) staining, scale bar: 100 μm. Tissue structures have been identified and labeled. Maintenance of original tissue organization, architecture, and cellular heterogeneity is observed. ¹¹⁰

FIGURE 3

Multi‐omics of single‐cells: methods and applications. Based on the measurements that are of interest, a combination of single‐cell technologies are available. Left). The major types of molecules related to central biological dogma. Centre) Single‐cell measurements based on profiling the genome, epigenome, transcriptome, and proteome shown in different colors. Right) Single‐cell multi‐omics approaches based on the combination of different single‐cell sequencing methods to profile multiple molecule types of a single‐cell simultaneously.