1. Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.
- Author
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Long D Jr, Chan M, Han M, Kamdar Z, Ma RK, Tsai PY, Francisco AB, Barrow J, Shackelford DB, Yarchoan M, McBride MJ, Orre LM, Vacanti NM, Gujral TS, and Sethupathy P
- Subjects
- Humans, Liver Neoplasms metabolism, Liver Neoplasms genetics, Liver Neoplasms pathology, Voltage-Dependent Anion Channels metabolism, Voltage-Dependent Anion Channels genetics, Proteomics methods, Female, Mitochondria metabolism, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Metabolomics methods, Amino Acids metabolism
- Abstract
Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with 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. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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