Proteomic profiling of colorectal liver metastases reveals histopathological response-specific molecular signatures of chemotherapy efficacy

Chemoresistance in treatment of colorectal liver metastases (CRLM) poses a major challenge in preventing disease relapse, with up to 80% of patients developing drug resistance over the course of treatment. Proteomic signatures of responsive vs. non-responsive metastases can provide insights into functional expression patterns, potentially identifying biomarkers for therapy efficacy. A total of 33 CRLM tissue samples from 31 patients were subjected to histopathological and proteomic analysis. The patients were included in the study after undergoing preoperative treatment (n = 28), including platinum-based chemotherapy (n = 19), non-platinum-based chemotherapy (n = 8), as well as targeted therapies (n = 20), or without preoperative therapy (n = 5). Based on Rubbia-Brandt criteria and vital tumor cell percentage, CRLM were categorized to major (MR), partial (PR) and no response (NR) groups. Proteomic analysis was conducted using label-free mass spectrometry (LFQ-MS), followed by clustering according to histological response and distinct treatment regimens. Proteomic analysis revealed significant differential protein expression of 607 proteins linked to distinct histopathological response types. CRLM responsive to chemotherapy displayed marked enrichment (p ≤ 0.01) in pathways associated with immune infiltration, ECM matrix organization, the complement system, and apolipoprotein-associated processes, indicative of distinct stromal and immune invasion patterns with multimodal importance of cell adhesion proteins. In contrast, attenuated expression of proteins enriched in pathways of mitochondrial translation initiation, elongation and termination was detectable. CRLM exhibited distinct proteomic phenotypes based on their histopathological response to preoperative systemic therapy largely independent of chemotherapy regimens. This proteomic profiling establishes a foundation for identifying critical biomarker profiles by nominating protein markers for major chemotherapy response.