Dataset Information

Proteomic Profiling of Colorectal Liver Metastases Reveals Histopathological Response-Specific Molecular Signatures of Chemotherapy Efficacy

ABSTRACT: Background: Chemoresistance in treatment of colorectal liver metastases (CRLM) poses a serious 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. Methods: 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. Results: 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, complement system, ECM matrix organization 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. Conclusion: 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 profiles and enhancing our understanding of mechanisms driving tumor response.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colorectal Cancer Cell

SUBMITTER: Karl Hillebrandt

LAB HEAD: Karl Hillebrandt

PROVIDER: PXD065812 | Pride | 2026-04-13

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	KH-A004-CRLM2_lfNr_00_PO-DDA_RA2_1_131.d.zip	Other
	KH-A004-CRLM2_lfNr_19_P07_RA3_1_133.d.zip	Other
	KH-A004-CRLM2_lfNr_20_P08_RA4_1_134.d.zip	Other
	KH-A004-CRLM2_lfNr_21_P09_RA5_1_135.d.zip	Other
	KH-A004-CRLM2_lfNr_22_P10_RA6_1_136.d.zip	Other

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Publications

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

Böhm Agnes K AK Skrip Lisa M LM Klein Oliver O Strobl Felix F Wieland Jonas K JK Arnold Alexander A Zhou Yijun Y Papke Björn B Sers Christine C Modest Dominik P DP Moosburner Simon S Haber Philipp K PK Krenzien Felix F Raschzok Nathanael N Schöning Wenzel W Horst David D Malinka Thomas T Sack Ingolf I Pratschke Johann J Sauer Igor M IM Hillebrandt Karl H KH

Journal of translational medicine 20260305 1

PMID: 41787508

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Project description:Colorectal carcinoma is a major global disease with the second highest mortality rate among carcinomas. The liver is the most common site for metastases which portends a poor prognosis. Nonetheless, considerable heterogeneity of colorectal cancer liver metastases (CRC-LM) exists, evidenced by varied recurrence and survival patterns in patients undergoing curative-intent resection. Our understanding of the basis for this biological heterogeneity is limited. We investigated this by proteomic analysis of 152 CRC-LM obtained from three different medical centres in Germany and Australia using mass spectrometry based differential quantitative proteomics. The proteomics data of the individual cohorts were harmonized through batch-effect correction algorithms to build a large multi-center cohort. Applying ConsensusClusterPlus to the proteome data yielded three distinct CRC-LM phenotypes (referred to as CRLM-SD, CRLM-CA and CRLM-OM). The CRLM-SD phenotype showed higher abundance of key regulators of alternative splicing as well as extracellular matrix proteins commonly associated with tumour cell growth. The CRLM-CA phenotype was characterized by a higher abundance of proteins involved in the classical pathway part of the complement system including the membrane attack complex proteins and those with anti-thrombotic activity. The CRLM-OM phenotype showed higher abundance of proteins involved in various metabolic pathways including amino acids and fatty acids metabolism, which correlated in the literature with advanced proliferation of metastases and increased recurrence. Patients classified as CRLM-OM had a significantly lower progression-free survival in comparison to CRLM-CA patients. Finally, we identified a set of prognosis-associated biomarkers for each group including EpCAM, CEACAM1, CEACAM5 and CEACAM6 for CRLM-SD, DCN, TIMP3 and OLFM4 for CRLM-CA and FMO3, CES2 and AGXT for CRLM-OM. In summary, the discovery of three proteomic subgroups associated with distinct signalling pathways and survival of the CRC-LM patients provides a novel classification for risk stratification, prognosis and potentially novel therapeutic targets in CRC-LM.

Project description:Background: Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression profiling to delineate major deregulated pathways and biomarkers associated with the development of intrinsic chemotherapy resistance upon exposure to standard first-line therapy for ovarian cancer. Methods: The study cohort comprised 28 patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. All 28 patients had advanced stage, high-grade serous ovarian cancer, and were treated with the same standard platinum-based chemotherapy. Twelve patient tumors demonstrating relative resistance to platinum chemotherapy corresponding to shorter PFS (< eight months) were compared to sixteen tumors from platinum-sensitive patients (PFS > eighteen months). Whole transcriptome profiling was performed using a Affymetrix high-resolution microarray platform to permit global comparisons of gene expression profiles between tumors from the resistant group and the sensitive group. Results: Microarray data analysis revealed a set of 204 discriminating genes possessing expression levels, which could influence differential chemotherapy response between the two groups. Robust statistical testing was then performed which eliminated a dependence on the normalization algorithm employed, producing a restricted list of differentially regulated genes, and which found IGF1 to be the most strongly differentially expressed gene. Pathway analysis, based on the list of 204 genes, revealed enrichment in genes primarily involved in the IGF1/PI3K/NFκB/ERK gene signalling networks. Conclusions: This study has identified pathway specific prognostic biomarkers possibly underlying a differential chemotherapy response in patients undergoing standard platinum-based treatment of serous epithelial ovarian cancer. Future studies to validate these markers are necessary to apply this knowledge to biomarker-based clinical trials. Total RNA from 12 chemotherapy resistant and 16 sensitive chemotherapy sensitive high-grade serous epithelial ovarian cancer samples was subjected to whole transcriptome profiling using Affymetrix U133 Plus 2.0 arrays