Proteomic profiling in fibrolamellar carcinoma patient tumor tissue

ABSTRACT: Fibrolamellar carcinoma (FLC) is a rare, early-onset liver cancer. The five-year survival rate is low, and there is a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. To date, only one study has attempted to characterize the FLC proteome and metabolome, but with modest sample size (proteomics—n = 16 patient samples; metabolomics—n = 10 patient samples) and protein detection (n = 4620 proteins). We have performed the most comprehensive characterization of FLC in both proteomics (n = 23 patient samples; n = 8485 proteins) and metabolomics (n = 26 patient samples; n = 135 metabolites). Additionally, we have conducted respirometry analyses as well as RNAi- and small molecule inhibitor-mediated loss of function assays in FLC tumors and non-malignant liver tissue from patients. We propose a model of cellular energetics in FLC that centers on amino acids. Our model points to proline anabolism that is very likely mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism providing the starting substrate. The metabolic rewiring in FLC proposed by our model, with a particular emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

DISEASE(S): Fibrolamellar Carcinoma

SUBMITTER: José Eduardo Araújo  

LAB HEAD: Janne Lehtiö

PROVIDER: PXD051527 | Pride | 2025-05-06

REPOSITORIES: Pride