Charting the Heterogeneity of Colorectal Cancer Consensus Molecular Subtypes using Spatial Transcriptomics

Abstract

The heterogeneity of colorectal cancer (CRC) contributes to substantial differences in patient response to standard therapies. The consensus molecular subtypes (CMS) of CRC is the most widely-used gene expression-based classification and has contributed to a better understanding of disease heterogeneity and prognosis. Nevertheless, CMS intratumoral heterogeneity restricts its clinical application, stressing the necessity of further characterizing the composition and architecture of CRC. Here, we used Spatial Transcriptomics (ST) in combination with single-cell RNA sequencing (scRNA-seq) to decipher the spatially resolved cellular and molecular composition of CRC. In addition to mapping the intratumoral heterogeneity of CMS and their microenvironment, we identified cell communication events in the tumor-stroma interface of CMS2 carcinomas. This includes tumor growth-inhibiting as well as -activating signatures, such as the potential regulation of the ETV4 transcriptional activity by DCN or the PLAU-PLAUR ligand-receptor interaction. Our data show the power of ST to bring the CMS-based classification of CRC to another level and thereby gain useful molecular insights for personalized therapy.

Competing Interest Statement

AV, BA, EG, NG, MR, SB, IW, LV, EY, MB, MS, NK, BJ, PS, TB and KH are currently employed by F. Hoffmann-La Roche Ltd. AJL and DT were previously employed by F. Hoffmann-La Roche Ltd. AJL is currently employed by Idorsia Pharmaceuticals Ltd. DT is currently employed by University of Bern. AL is currently employed by Genentech, Inc. MDT was previously employed by Genentech, Inc and is currently employed by Gilead Sciences, Inc. JSR has received funding from GSK and Sanofi and fees from Travere Therapeutics and Astex Pharmaceuticals. The authors declare that they have no other competing interests.

Footnotes

* We have introduced some minor changes into the original version as a result of feedback upon publication of the first version. In particular, we have detailed that one of the ligand-receptor interactions described in the first version may actually correspond to an intra-cellular effect rather than a cell communication effect.