Transcriptomics and proteomics reveal distinct biology for lymph node metastases and tumor deposits in colorectal cancer

ABSTRACT: Objective: Both lymph node metastases (LNMs) and tumor deposits (TDs) are included in colorectal cancer (CRC) staging, although knowledge regarding their biological background is lacking. This study aims to compare the biology of these prognostic features, which is essential for a better understanding of their role in CRC spread. Design: Spatially resolved transcriptomic analysis using Digital Spatial Profiling was performed on TDs and LNMs from 10 CRC patients using 1,388 RNA targets, for the tumor cells and tumor microenvironment (TME). Shotgun proteomics identified 5,578 proteins in 12 different patients. Differences in RNA and protein expression were analyzed, and spatial deconvolution was performed. Image-based CMS (imCMS) analysis was performed on all TDs and LNMs included in the study. Results: Transcriptome and proteome profiles identified distinct clusters for TDs and LNMs in both the tumor and TME segment, with upregulation of matrix remodeling, cell adhesion/motility and epithelial mesenchymal transition (EMT) in TDs (all p<0.05). Spatial deconvolution showed a significantly increased number of fibroblasts, macrophages, and regulatory T cells (p<0.05) in TDs. In consistency with a higher fibroblast and EMT component, imCMS classified 62% of TDs as poor prognosis subtype CMS4 compared to 36% of LNMs (p<0.05). Conclusion: Compared to LNMs, TDs have a more invasive state; involving a distinct TME and upregulation of EMT, which are reflected in a more frequent histological classification of TDs as CMS4. These results emphasize the heterogeneity of locoregional spread the fact that TDs should merit more attention both in future research and during staging.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colorectal Cancer Cell

DISEASE(S): Colorectal Cancer

SUBMITTER: Pascal Jansen  

LAB HEAD: Michiel Vermeulen

PROVIDER: PXD041625 | Pride | 2023-09-19

REPOSITORIES: Pride