Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma

Solomon N. Levin; Michael D. Tomasini; James Knox; Mahsa Shirani; Bassem Shebl; David Requena; Jackson Clark; Søren Heissel; Hanan Alwaseem; Rodrigo Surjan; Ron Lahasky; Henrik Molina; Michael S. Torbenson; Barbara Lyons; Rachael D. Migler; Philip Coffino; Sanford M. Simon

doi:10.1126/sciadv.adg7038

Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma

Solomon N. Levin, Michael D. Tomasini, James Knox, Mahsa Shirani, Bassem Shebl, David Requena, Jackson Clark, Søren Heissel, Hanan Alwaseem, Rodrigo Surjan, Ron Lahasky, Henrik Molina, Michael S. Torbenson, Barbara Lyons, Rachael D. Migler, Philip Coffino, Sanford M. Simon

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

Abstract

Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis. Hyperammonemic encephalopathy is a recurrent problem in these patients, and established treatments based on the assumption of liver failure are unsuccessful. We show that many of the enzymes that produce ammonia are increased and those that consume ammonia are decreased.We also demonstrate that the metabolites of these enzymes change as expected. Thus, hyperammonemic encephalopathy in FLC may require alternative therapeutics.

Original language	English (US)
Article number	adg7038
Journal	Science Advances
Volume	9
Issue number	25
DOIs	https://doi.org/10.1126/sciadv.adg7038
State	Published - Jun 2023

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Levin, S. N., Tomasini, M. D., Knox, J., Shirani, M., Shebl, B., Requena, D., Clark, J., Heissel, S., Alwaseem, H., Surjan, R., Lahasky, R., Molina, H., Torbenson, M. S., Lyons, B., Migler, R. D., Coffino, P., & Simon, S. M. (2023). Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma. Science Advances, 9(25), Article adg7038. https://doi.org/10.1126/sciadv.adg7038

Levin, SN, Tomasini, MD, Knox, J, Shirani, M, Shebl, B, Requena, D, Clark, J, Heissel, S, Alwaseem, H, Surjan, R, Lahasky, R, Molina, H, Torbenson, MS, Lyons, B, Migler, RD, Coffino, P & Simon, SM 2023, 'Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma', Science Advances, vol. 9, no. 25, adg7038. https://doi.org/10.1126/sciadv.adg7038

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title = "Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma",

abstract = "Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis. Hyperammonemic encephalopathy is a recurrent problem in these patients, and established treatments based on the assumption of liver failure are unsuccessful. We show that many of the enzymes that produce ammonia are increased and those that consume ammonia are decreased.We also demonstrate that the metabolites of these enzymes change as expected. Thus, hyperammonemic encephalopathy in FLC may require alternative therapeutics.",

author = "Levin, {Solomon N.} and Tomasini, {Michael D.} and James Knox and Mahsa Shirani and Bassem Shebl and David Requena and Jackson Clark and S{\o}ren Heissel and Hanan Alwaseem and Rodrigo Surjan and Ron Lahasky and Henrik Molina and Torbenson, {Michael S.} and Barbara Lyons and Migler, {Rachael D.} and Philip Coffino and Simon, {Sanford M.}",

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doi = "10.1126/sciadv.adg7038",

language = "English (US)",

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AU - Levin, Solomon N.

AU - Tomasini, Michael D.

AU - Knox, James

AU - Shirani, Mahsa

AU - Shebl, Bassem

AU - Requena, David

AU - Clark, Jackson

AU - Heissel, Søren

AU - Alwaseem, Hanan

AU - Surjan, Rodrigo

AU - Lahasky, Ron

AU - Molina, Henrik

AU - Torbenson, Michael S.

AU - Lyons, Barbara

AU - Migler, Rachael D.

AU - Coffino, Philip

AU - Simon, Sanford M.

PY - 2023/6

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AB - Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis. Hyperammonemic encephalopathy is a recurrent problem in these patients, and established treatments based on the assumption of liver failure are unsuccessful. We show that many of the enzymes that produce ammonia are increased and those that consume ammonia are decreased.We also demonstrate that the metabolites of these enzymes change as expected. Thus, hyperammonemic encephalopathy in FLC may require alternative therapeutics.

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Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma

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