Proteomic profiling and network biology of colorectal cancer liver metastasis

ABSTRACT

Introduction

Tissue-based proteomic studies of colorectal cancer (CRC) metastasis have delivered fragmented results, with very few therapeutic targets and prognostic biomarkers moving beyond the discovery phase. This situation is likely due to the difficulties in obtaining and analyzing large numbers of patient-derived metastatic samples, the own heterogeneity of CRC, and technical limitations in proteomics discovery. As an alternative, metastatic CRC cell lines provide a flexible framework to investigate the underlying mechanisms and network biology of metastasis for target discovery.

Areas Covered

In this perspective, we comment on different in-depth proteomic studies of metastatic versus non-metastatic CRC cell lines. Identified metastasis-related proteins are introduced and discussed according to the spatial location in different cellular fractions, with special emphasis on membrane/adhesion proteins, secreted proteins, and nuclear factors, including miRNAs associated with liver metastasis. Moreover, we analyze the biological significance and potential therapeutic applications of the identified liver metastasis-related proteins.

Expert Opinion

The combination of protein discovery and functional analysis is the only way to accelerate the progress to clinical translation of the proteomic-derived findings in a relatively fast pace. Patient-derived organoids represent a promising alternative to patient tissues and cell lines, but further optimizations are still required for achieving solid and reproducible results.

KEYWORDS:

• Colorectal cancer
• metastasis
• quantitative proteomics
• Interactomics
• therapeutic targets

Article highlights

• Despite some known limitations, paired metastatic vs non-metastatic cell lines still constitute the most suitable model for proteomic profiling and for deciphering molecular mechanisms underlying colorectal liver metastasis.

• The application of fractionation techniques to isolate the different cell compartments has significantly improved the amount and relevance of the deregulated proteins identified in metastatic cells.

• The proteomic analyses of cancer cell lines differing in their metastatic potential have demonstrated to be a rich source for the discovery of novel prognostic biomarkers and therapeutic targets against metastatic colorectal cancer.

• A number of relevant proteins in CRC liver metastasis: CDH17, IL13Rα2, SOSTDC1, ZG16B, and SRSF3, among others, have been identified by proteomic analysis of metastatic cell lines, functionally characterized and tested for therapeutic targeting.

• Future advances in colorectal liver metastasis should rely on the optimization and massive use of patient-derived organoid biobanks for multi-omic characterization.

Reviewer disclosures

Peer reviewers of this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

JI Casal has stock ownership of Protein Alternatives SL. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

JI Casal was funded by grants PID2021-122227OB-I00, CPP2021-008337, and PDC2022-133056-I00 from the MCIN/AEI/10.13039/501100011033 and by the Next-Generation EU/PRTR and PMPTA22/00108 from the Instituto de Salud Carlos III.