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BRAF Modulates Lipid Use and Accumulation

SIMPLE SUMMARY: BRAF is a serine/threonine kinase that is commonly mutated across cancers. The BRAF V600E mutation is targetable with kinase inhibitors; however, many patients eventually develop resistance. Recent evidence suggests that tumors harboring BRAF mutations may oxidize fatty acids for ene...

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Autores principales: Turner, Jacqueline A., Paton, Emily L., Van Gulick, Robert, Stefanoni, Davide, Cendali, Francesca, Reisz, Julie, Tobin, Richard P., McCarter, Martin, D’Alessandro, Angelo, Torres, Raul M., Robinson, William A., Couts, Kasey L., Schlaepfer, Isabel R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105200/
https://www.ncbi.nlm.nih.gov/pubmed/35565240
http://dx.doi.org/10.3390/cancers14092110
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author Turner, Jacqueline A.
Paton, Emily L.
Van Gulick, Robert
Stefanoni, Davide
Cendali, Francesca
Reisz, Julie
Tobin, Richard P.
McCarter, Martin
D’Alessandro, Angelo
Torres, Raul M.
Robinson, William A.
Couts, Kasey L.
Schlaepfer, Isabel R.
author_facet Turner, Jacqueline A.
Paton, Emily L.
Van Gulick, Robert
Stefanoni, Davide
Cendali, Francesca
Reisz, Julie
Tobin, Richard P.
McCarter, Martin
D’Alessandro, Angelo
Torres, Raul M.
Robinson, William A.
Couts, Kasey L.
Schlaepfer, Isabel R.
author_sort Turner, Jacqueline A.
collection PubMed
description SIMPLE SUMMARY: BRAF is a serine/threonine kinase that is commonly mutated across cancers. The BRAF V600E mutation is targetable with kinase inhibitors; however, many patients eventually develop resistance. Recent evidence suggests that tumors harboring BRAF mutations may oxidize fatty acids for energy rather than utilizing aerobic glycolysis (the Warburg effect). Understanding the metabolism of cells harboring BRAF mutations may uncover targets to improve therapy response. We studied the effects of BRAF mutation and expression on metabolism. We found that cell expressing BRAF V600E were enriched with immunomodulatory lipids and have a metabolism that is distinct from cells expressing wild type BRAF. We also found that patients with melanoma who did not respond to BRAF-targeted therapy had plasma lipid profiles that were different from patients who responded to this therapy. Overall, our findings indicate that targeting lipid metabolism may be a potential alternative strategy to improve patient responses to BRAF-targeted therapies. ABSTRACT: There is increasing evidence that oxidative metabolism and fatty acids play an important role in BRAF-driven tumorigenesis, yet the effect of BRAF mutation and expression on metabolism is poorly understood. We examined how BRAF mutation and expression modulates metabolite abundance. Using the non-transformed NIH3T3 cell line, we generated cells that stably overexpressed BRAF V600E or BRAF WT. We found that cells expressing BRAF V600E were enriched with immunomodulatory lipids. Further, we found a unique transcriptional signature that was exclusive to BRAF V600E expression. We also report that BRAF V600E mutation promoted accumulation of long chain polyunsaturated fatty acids (PUFAs) and rewired metabolic flux for non-Warburg behavior. This cancer promoting mutation further induced the formation of tunneling nanotube (TNT)-like protrusions in NIH3T3 cells that preferentially accumulated lipid droplets. In the plasma of melanoma patients harboring the BRAF V600E mutation, levels of lysophosphatidic acid, sphingomyelin, and long chain fatty acids were significantly increased in the cohort of patients that did not respond to BRAF inhibitor therapy. Our findings show BRAF V600 status plays an important role in regulating immunomodulatory lipid profiles and lipid trafficking, which may inform future therapy across cancers.
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spelling pubmed-91052002022-05-14 BRAF Modulates Lipid Use and Accumulation Turner, Jacqueline A. Paton, Emily L. Van Gulick, Robert Stefanoni, Davide Cendali, Francesca Reisz, Julie Tobin, Richard P. McCarter, Martin D’Alessandro, Angelo Torres, Raul M. Robinson, William A. Couts, Kasey L. Schlaepfer, Isabel R. Cancers (Basel) Article SIMPLE SUMMARY: BRAF is a serine/threonine kinase that is commonly mutated across cancers. The BRAF V600E mutation is targetable with kinase inhibitors; however, many patients eventually develop resistance. Recent evidence suggests that tumors harboring BRAF mutations may oxidize fatty acids for energy rather than utilizing aerobic glycolysis (the Warburg effect). Understanding the metabolism of cells harboring BRAF mutations may uncover targets to improve therapy response. We studied the effects of BRAF mutation and expression on metabolism. We found that cell expressing BRAF V600E were enriched with immunomodulatory lipids and have a metabolism that is distinct from cells expressing wild type BRAF. We also found that patients with melanoma who did not respond to BRAF-targeted therapy had plasma lipid profiles that were different from patients who responded to this therapy. Overall, our findings indicate that targeting lipid metabolism may be a potential alternative strategy to improve patient responses to BRAF-targeted therapies. ABSTRACT: There is increasing evidence that oxidative metabolism and fatty acids play an important role in BRAF-driven tumorigenesis, yet the effect of BRAF mutation and expression on metabolism is poorly understood. We examined how BRAF mutation and expression modulates metabolite abundance. Using the non-transformed NIH3T3 cell line, we generated cells that stably overexpressed BRAF V600E or BRAF WT. We found that cells expressing BRAF V600E were enriched with immunomodulatory lipids. Further, we found a unique transcriptional signature that was exclusive to BRAF V600E expression. We also report that BRAF V600E mutation promoted accumulation of long chain polyunsaturated fatty acids (PUFAs) and rewired metabolic flux for non-Warburg behavior. This cancer promoting mutation further induced the formation of tunneling nanotube (TNT)-like protrusions in NIH3T3 cells that preferentially accumulated lipid droplets. In the plasma of melanoma patients harboring the BRAF V600E mutation, levels of lysophosphatidic acid, sphingomyelin, and long chain fatty acids were significantly increased in the cohort of patients that did not respond to BRAF inhibitor therapy. Our findings show BRAF V600 status plays an important role in regulating immunomodulatory lipid profiles and lipid trafficking, which may inform future therapy across cancers. MDPI 2022-04-23 /pmc/articles/PMC9105200/ /pubmed/35565240 http://dx.doi.org/10.3390/cancers14092110 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Turner, Jacqueline A.
Paton, Emily L.
Van Gulick, Robert
Stefanoni, Davide
Cendali, Francesca
Reisz, Julie
Tobin, Richard P.
McCarter, Martin
D’Alessandro, Angelo
Torres, Raul M.
Robinson, William A.
Couts, Kasey L.
Schlaepfer, Isabel R.
BRAF Modulates Lipid Use and Accumulation
title BRAF Modulates Lipid Use and Accumulation
title_full BRAF Modulates Lipid Use and Accumulation
title_fullStr BRAF Modulates Lipid Use and Accumulation
title_full_unstemmed BRAF Modulates Lipid Use and Accumulation
title_short BRAF Modulates Lipid Use and Accumulation
title_sort braf modulates lipid use and accumulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105200/
https://www.ncbi.nlm.nih.gov/pubmed/35565240
http://dx.doi.org/10.3390/cancers14092110
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