Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.

Autor:	Long D Jr; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. Electronic address: dl964@cornell.edu., Chan M; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA., Han M; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA., Kamdar Z; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Ma RK; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA., Tsai PY; Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA., Francisco AB; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA., Barrow J; Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA., Shackelford DB; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA., Yarchoan M; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA., McBride MJ; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA., Orre LM; Department of Oncology and Pathology, Karolinska Institute, SciLifeLab, Solna, Sweden., Vacanti NM; Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA., Gujral TS; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA., Sethupathy P; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. Electronic address: pr46@cornell.edu.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Sep 17; Vol. 5 (9), pp. 101699. Date of Electronic Publication: 2024 Aug 28.
DOI:	10.1016/j.xcrm.2024.101699
Abstrakt:	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.)
Databáze:	MEDLINE
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