Organized proteomic heterogeneity in colorectal liver metastases and implications for therapies

Introduction : Tumor heterogeneity is a major obstacle for developing effective anti-cancer treatments. Recent studies have pointed at large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach.
Aim : Because to date no similar information is available at the protein (phenotype) level, we aimed at characterising the proteomic heterogeneity in human colorectal carcinoma (CRC) liver metastases.
Methods & Results : We employed MALDI imaging-guided proteomics and explored the heterogeneity of extracellular distribution of over 1000 proteins we found unexpectedly that all liver metastasis lesions displayed a reproducible, zon- ally delineated, pattern of functional and therapeutic biomarker heterogeneity. 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.
Conclusions : proteome heterogeneity has a distinct, organized, pattern. This particular hallmark can now be used as a part of the strategy for developing rational therapies based on multiple sets of targetable antigens.