Organized proteomic heterogeneity in colorectal cancer liver metastases and implications for therapies

• DOI: 10.1002/hep.26608
• Publication Date: 2013-07-06T04:57:04Z
• Authors: Andrei Turtoi; Arnaud Blomme; Delphine Debois; Joan Somja; David Delvaux; Georgios Patsos; Emmanuel Di Valentin; Olivier Peulen; Eugène Nzaramba M...; Edwin De Pauw; Philippe Delvenne; Olivier Detry; Vincent Castronovo
• Keywords: Proteomics; 0301 basic medicine; 0303 health sciences; Liver Neoplasms; Lipid Metabolism; High-Throughput Screening Assays; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; 03 medical and health sciences; 0302 clinical medicine; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Humans; Colorectal Neoplasms

Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach. Because to date no similar information is available at the protein (phenotype) level, we employed matrix assisted laser desorption ionization (MALDI) image-guided proteomics and explored the heterogeneity of extracellular and membrane subproteome in a unique collection of eight fresh human colorectal carcinoma (CRC) liver metastases. Monitoring the spatial distribution of over 1,000 proteins, we found unexpectedly that all liver metastasis lesions displayed a reproducible, zonally delineated pattern of functional and therapeutic biomarker heterogeneity. The peritumoral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis displayed increased cellular growth, movement, and drug metabolism, whereas the center of the lesion was characterized by elevated carbohydrate metabolism and DNA-repair activity. From the aspect of therapeutic targeting, zonal expression of known and novel biomarkers was evident, reinforcing the need to select several targets in order to achieve optimal coverage of the lesion. Finally, we highlight two novel antigens, LTBP2 and TGFBI, whose expression is a consistent feature of CRC liver metastasis. We demonstrate their in vivo antibody-based targeting and highlight their potential usefulness for clinical applications. Conclusion: The proteome heterogeneity of human CRC liver metastases has a distinct, organized pattern. This particular hallmark can now be used as part of the strategy for developing rational therapies based on multiple sets of targetable antigens. (HEPATOLOGY 2014;59:924–934)