Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

Abstract

Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.

People
Lu, Yuting
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Travnickova, Jana
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Badonyi, Mihaly
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Rambow, Florian
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Coates, Andrea
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Khan, Zaid
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Marques, Jair
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Murphy, Laura C.
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Garcia-Martinez, Pablo
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Marais, Richard
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Louphrasitthiphol, Pakavarin
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Chan, Alex H.Y.
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Schofield, Christopher J.
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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von Kriegsheim, Alex
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Marsh, Joseph A.
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Pavet, Valeria
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Sansom, Owen
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

Pereira, Brooke A. and Ritchie, Shona and Chambers, Cecilia R. and Gordon, Katie A. and Magenau, Astrid and Murphy, Kendelle J. and Nobis, Max and Tyma, Victoria M. and Liew, Ying Fei and Lucas, Morghan C. and Naeini, Marjan M. and Barkauskas, Deborah S. and Chacon-Fajardo, Diego and Howell, Anna E. and Parker, Amelia L. and Warren, Sean C. and Reed, Daniel A. and Lee, Victoria and Metcalf, Xanthe L. and Lee, Young Kyung and O'Regan, Luke P. and Zhu, Jessie and Trpceski, Michael and Fontaine, Angela R.M. and Stoehr, Janett and Rouet, Romain and Lin, Xufeng and Chitty, Jessica L. and Porazinski, Sean and Wu, Sunny Z. and Filipe, Elysse C. and Cadell, Antonia L. and Holliday, Holly and Yang, Jessica and Papanicolaou, Michael and Lyons, Ruth J. and Zaratzian, Anaiis and Tayao, Michael and Da Silva, Andrew and Vennin, Claire and Yin, Julia and Dew, Alysha B. and McMillan, Paul J. and Goldstein, Leonard D. and Deveson, Ira W. and Croucher, David R. and Samuel, Michael S. and Sim, Hao-Wen and Batten, Marcel and Chantrill, Lorraine and Grimmond, Sean M. and Gill, Anthony J. and Samra, Jaswinder and Evans, Thomas R. Jeffry and Sasaki, Takako and Phan, Tri G. and Swarbrick, Alexander and Sansom, Owen J. and Morton, Jennifer P. and Australian Pancreatic Cancer Matrix Atlas (APMA) and Australian Pancreatic Cancer Genome Initiative (APGI) and Pajic, Marina and Parker, Benjamin L. and Herrmann, David and Cox, Thomas R. and Timpson, Paul (2024) Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response. Science Advances, 10 (27): eadl1197. ISSN 2375-2548

Malla, Sudhir B. and Byrne, Ryan M. and Lafarge, Maxime W. and Corry, Shania M. and Fisher, Natalie C. and Tsantoulis, Petros K. and Mills, Megan L. and Ridgway, Rachel A. and Lannagan, Tamsin R. M. and Najumudeen, Arafath K. and Gilroy, Kathryn L. and Amirkhah, Raheleh and Maguire, Sarah L. and Mulholland, Eoghan J. and Belnoue-Davis, Hayley L. and Grassi, Elena and Viviani, Marco and Rogan, Emily and Redmond, Keara L. and Sakhnevych, Svetlana and McCooey, Aoife J. and Bull, Courtney and Hoey, Emily and Sinevici, Nicoleta and Hall, Holly and Ahmaderaghi, Baharak and Domingo, Enric and Blake, Andrew and Richman, Susan D. and Isella, Claudio and Miller, Crispin and Bertotti, Andrea and Trusolino, Livio and Loughrey, Maurice B. and Kerr, Emma M. and Tejpar, Sabine and S:CORT Consortium and Maughan, Timothy S. and Lawler, Mark and Campbell, Andrew D. and Leedham, Simon J. and Koelzer, Viktor H. and Sansom, Owen J. and Dunne, Philip D. (2024) Author Correction: Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics, 56 (6): 1321. ISSN 1061-4036

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Illingworth, Robert S.
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Patton, E. Elizabeth
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

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Title:
ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma
Creators:
Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth
Identification Number:
10.1016/j.celrep.2024.114406
Date:
23 July 2024
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
Elsevier (Cell Press)
Additional Information:
We acknowledge the following funding: RSI: MRC Career Development award (MR/S007644/1) and the Simons Initiative for the Developing Brain (SFARI - 529085); A.V.K., Wellcome Trust (Multiuser Equipment 208402/Z/ 17); Z.K., Melville Trust for Cancer Research (studentship M00109.0001/ TZH/MHR); F.R., Melanoma Research Alliance and the Wolfgang & Gertrud Boettcher Foundation; J.A.M., European Research Council (101001169); C.J.S., CRUK (C8717/A18245 and C8717/A28285) and the Wellcome Trust (106244/Z/14/Z); and E.E.P., Medical Research Council (MC_UU_00035/13), the European Research Council (ZF-MEL-CHEMBIO-648489), and Melanoma Research Alliance and Rosetrees Trust (MRA Awards 687306 and 917226). The generation of patient-derived cell lines was supported by funds from the Wellcome Trust (100282/Z/12/Z) to R.M. This work was supported by the CRUK Scotland Centre (CTRQQR-2021\100006).
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https://pub.demo35.eprints-hosting.org/id/eprint/190
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Date Deposited:
11 Jun 2025 16:35
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