Multi-omics in colorectal cancer liver metastasis: applications and research advances

Abstract

Colorectal cancer (CRC) is a common malignant tumor with a high mortality rate worldwide. Advanced CRC often leads to liver metastasis, which has a poor prognosis, highlighting the need to investigate the underlying mechanisms. Omics, encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics, enables comprehensive molecular analysis of cells and tissues. Tumor-omics research has advanced rapidly, with growing attention on CRC-related omics. However, systematic reviews on omics research specific to colorectal cancer liver metastasis (CRLM) are limited. This review summarizes the current status and progress of multi-omics research on CRLM and discusses the application of multi-omics technologies in basic research and the significant clinical implications.

Keywords: Colorectal cancer liver metastasis; epigenomics; genomics; metabolomics; microbiomics; proteomics; transcriptomics.

Figure 1

Omics framework of colorectal cancer liver metastasis. Genomic, epigenetic, transcriptomic, proteomic, metabolomic, and microbiomic analyses were performed on tissue from primary colorectal cancer lesions (T), liver metastases (LM), lymph node metastases (NM), blood circulation (BC), and fecal microbiota (FM) samples.

Figure 2

Epigenetic regulation in colorectal cancer (CRC) and CRC liver metastasis (CRLM). (A) Histone modifications as potential diagnostic biomarkers for CRC. Trimethylation of H3K9 and H3K27 enhances the expression of immune checkpoint genes, such as CTLA-4, TIGIT, PD-1, and TIM-3, which may serve as epigenetic markers for CRC. Methylation signatures on circulating nucleosomal histones, including H3K27me3 and H4K20me3, are detectable in the bloodstream and have potential diagnostic value. Differences in HIST2H3AK19Ac and H2BLK121Ac acetylation between primary CRC tumors and liver metastases may serve as biomarkers of CRC progression. (B) Schematic representation of histone modifications. Histone methylation, acetylation, and phosphorylation are dynamically regulated by histone methyltransferases (HMTs), histone demethylases (HDMs), histone acetyltransferases (HATs), histone deacetylases (HDACs), protein kinases (PKs), and protein phosphatases (PPs), resulting in chromatin remodeling toward either an open (active) or closed (repressive) state. (C) Role of DNA methylation in CRLM. Aberrant DNA methylation alters gene expression by promoting either transcriptional activation or repression, contributing to the progression of liver metastasis in CRC. (D) Schematic of epigenetic regulation via chromatin remodeling. Epigenetic mechanisms, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs), mediate chromatin structure reorganization, thereby influencing gene accessibility and transcriptional activity. B3GNT7, beta-1,3-N-acetylglucosaminyltransferase 7; CAB39, calcium-binding protein 39; C2, complement component 2; CEP112, centrosomal protein 112; CFLAR, CASP8 and FADD-like apoptosis regulator; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CTSC, cathepsin C; EVI2B, ecotropic viral integration site 2B; GUF1, GUF1 homolog, GTPase; KLF4, Kruppel-like factor 4; LZTS1, leucine zipper tumor suppressor 1; MAPT, microtubule-associated protein tau; MUC2, mucin 2; PAX8, paired box 8; PD-1, programmed cell death protein 1; PTH1R, parathyroid hormone 1 receptor; RASSF1A, ras association domain family member 1 isoform A; SHANK2, SH3 and multiple ankyrin repeat domains 2; SLC10A1, solute carrier family 10 member 1; THBS1, thrombospondin 1; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; TIM3, T-cell immunoglobulin and mucin-domain containing-3; TNNI2, troponin I2, fast skeletal type; TRAPPC3, trafficking protein particle complex subunit 3; UPK3A, uroplakin 3A.

Figure 3

Microbiomics of colorectal cancer liver metastasis (CRLM). Microbiome-related techniques have identified the presence of Proteus mirabilis, Bacteroides vulgatus, and Fusobacterium nucleatum in the primary colorectal cancer (CRC) lesions. Fusobacterium nucleatum is also detected within CRLM sites, where its presence is associated with reduced infiltration of CD8+ T cells and increased accumulation of myeloid-derived suppressor cells (MDSCs). Therapeutic approaches, such as oral administration of metronidazole (MNZ) and a nanoengineered probiotic delivery system (LR-S-CD/CpG@LNP), have demonstrated efficacy in treating both primary CRC and CRLM. Fecal microbiota transplantation (FMT) has shown potential to synergize with PD-1 blockade therapy in CRLM.

Figure 4

Multi-omics analysis of colorectal cancer liver metastasis (CRLM). Integrated genomic, transcriptomic, and proteomic analyses have suggested a potential role of breast cancer gene 1 (BRCA1) in the early development of CRLM, indicating its promise as a tumor microenvironment (TME)-associated biomarker. Genomic and transcriptomic profiling has identified SMAD family member 4 (SMAD4) R361H/C mutations, which may confer resistance to bevacizumab and 5-fluorouracil (5-FU) via activation of the STAT3 signaling pathway. Four-jointed box 1 (FJX1) is considered to be a potential therapeutic target for CRLM through multi-omics analyses. Combined genomic and proteomic studies have also revealed that SMAD4, calponin-2, and glutathione peroxidase 3 may serve as predictive markers for early recurrence of CRLM.