Jiří Neužil

Malignant transformation is a prerequisite for the initiation and development of cancer. This process, although differing in different tumour types in terms of mutations and other parameters, is likely to be accompanied in a number of cancers by a major metabolic change. This metabolic reprogramming is important in terms of the very rapid proliferation of nascent cancer cells and is partly analogous to the metabolic changes in tissue re-generation, exemplified by the liver, which undergoes complete regeneration (including functional recovery) after partial (60-90%) hepatectomy (PHx) within 7 days. A major difference is that after regeneration is complete, the metabolism promoting rapid proliferation changes again to the ‘normal’ metabolism typical of homeostasis, whereas in cancer the metabolism promoting rapid proliferation persists. We hypothesize that altered metabolism is co-relevant to reversal in a number of cancers, which we demonstrate for diethylnitrosamine (DEN) administration-induced kidney cancer and for HER2+ breast cancer using a transgenic c-neu mouse. We will use a sophisticated methodology to monitor changes in metabolism and other characteristic features of malignant transformation in liver and breast tissue. We will focus on the different stages of malignant transformation, from normal tissue to dysplastic tissue to invasive tumor tissue that eventually leads to metastatic disease. We collaborate with leading international facilities (e.g. MIT; NIH; Uni Cambridge; Malaghan Institute, Wellington, NZ).

Research objective

We focus on the following metabolic changes:

1. A switch from nucleotide formation (both pyrimidines and purines) in normal tissue via ‘salvage’ pathways to formation via kinetically more efficient de novo pathways. 
2. Reversal of the urate cycle during malignant transformation, where ammonia is not degraded by the liver to the waste product urea, but is metabolized to glutamine, a substrate for both nucleotides and amino acids, which are required for cellular biomass formation.
3. Regeneration of liver tissue after PHx, leading to the elimination of liver metastases. Here we use an orthotopic model of syngeneic colorectal tumors that metastasize to the liver. We use transgenic mice with induced knock-out of key genes, advanced imaging methods, a set of OMICs methods, and monitoring of metabolic pathways using stable isotopes (15NH4Cl, 13C515N2-Gln, etc.) using mass spectroscopy (MS). We also use metabolomic analysis on tissue sections using MALDI MS (repifleX).