From genes to proteins

"There is a strong need for new therapies other than surgery to treat patients with hepatic metastases. If we are able to discover an effective therapy for liver metastases, we could reduce the high mortality rates associated with cancer," says Andrei Turtoi. "The targeted therapies that have been developed so far work at first, but then the tumour takes back over," indicates the researcher. It is in this context and following these observations that Andrei Turtoi and his colleagues at the Metastasis Research Laboratory became interested in CRC liver metastases. The tumour and the metastases are very heterogeneous in terms of cell populations. Yet a given targeted therapy targets only one population of cells within the tumour that share the same target. "We are able to kill these cells, but the other populations of cancer cells escape unharmed. Following Darwin's theory of evolution, the fittest cancer cells surviving the selection pressure have an advantage and cause the tumour and metastases to regrow," explains Andrei Turtoi.

A number of studies have reported on the daunting genetic heterogeneity in cancer, but the Liège researchers wanted to know if this heterogeneity also existed at the protein level. "Cancer cells present many kinds of mutations, so it's difficult to know what to target and how," continues the researcher. "But we weren't targeting genes, we were targeting proteins," Andrei Turtoi reminds us.

Organised proteomic heterogeneity

In order to analyse the proteins in CRC liver metastases, the scientists worked in collaboration with the Department of Abdominal Surgery at Liège University Hospital and with GIGA's Mass Spectrometry and Experimental Pathology Laboratories. "We had the opportunity to study human liver metastases from colorectal carcinoma and thanks to a specific mass spectrometry imaging technique we were able to screen first for different peptides in the metastases. The advantage of this approach is that we didn't have to dissect and thus disturb the tumour," says Andrei Turtoi.
 
The research results that were published in the journal Hepatology(1) demonstrate that hepatic metastases do display proteomic heterogeneity, however this heterogeneity is actually organized. "The peptides are zonally delineated and these zones are very similar from one patient to another," the scientist reveals. The tumours are thus less phenotypically heterogeneous than expected given their genetic heterogeneity. "Although cancer cells carry different mutations, it seems that they can still behave in the same way," explains Andrei Turtoi. The zonal delineation can be explained by the fact that environmental factors in the tumor, such as oxygen and nutrient availability, favour certain phenotype. "This is very good news for targeted therapy because we can now envisage targeting the cells of the same zone together since they have the same phenotype," continues Andrei Turtoi.

(1) Andrei Turtoi, Arnaud Blomme, Delphine Debois, Joan Somja, David Delvaux, Georgios Patsos, Emmanuel Di Valentin, Olivier Peulen, Eugène Nzaramba Mutijima, Edwin De Pauw, Philippe Delvenne, Olivier Detry and Vincent Castronovo. Organized Proteomic Heterogeneity in Colorectal Cancer Liver Metastases and Implications for Therapies. Hepatology. 2013 Jul 6. doi: 10.1002/hep.26608.