Proteomic landscape of colorectal cancer liver metastasis.

[BACKGROUND] Colorectal cancer metastasis, especially liver metastasis, is characterized by significant intricate diversity and remains a major contributor to patient mortality. Despite its clinical importance, the precise molecular mechanisms driving metastasis remain poorly understood.

[METHODS] To investigate the molecular drivers of metastasis heterogeneity, we performed a comprehensive proteomic analysis of non-metastatic (NM) colorectal cancer tissues, as well as metachronous (MM) and synchronous (SM) metastatic tissues.

[RESULTS] Our analysis revealed distinct biological features associated with colorectal cancer liver metastasis. Notably, we identified P53-mediated hyperproliferation as a common initiating factor in the occurrence of CRC. Additionally, metabolic dysregulation emerged as a key hallmark of CRC liver metastasis. Importantly, MM tumors exhibited suppressed ferroptosis and activation of the TGF-β signaling pathway, while SM tumors displayed inhibited anoikis and activation of the WNT signaling pathway, accompanied by activated angiogenesis. Most strikingly, CEACAM6 was identified as the only protein exhibiting a stepwise decrease in expression from NM to MM and further to SM, underscoring its unique role in metastatic progression.

[CONCLUSIONS] These findings provide new insights into the molecular complexities underpinning colorectal cancer liver metastasis. Our identification of CEACAM6 as a differential marker highlights its potential as a diagnosis marker and therapeutic target, offering new avenues for the treatment of metastatic CRC.