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Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer

The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that likely contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical discovery st...

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Autores principales: Koo, Junghui, Seong, Chang-Soo, Parker, Rebecca E., Dwivedi, Bhakti, Arthur, Robert A., Dinasarapu, Ashok Reddy, Johnston, H. Richard, Claussen, Henry, Tucker-Burden, Carol, Ramalingam, Suresh S., Fu, Haian, Zhou, Wei, Marcus, Adam I., Gilbert-Ross, Melissa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312689/
https://www.ncbi.nlm.nih.gov/pubmed/37398244
http://dx.doi.org/10.1101/2023.06.14.544941
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author Koo, Junghui
Seong, Chang-Soo
Parker, Rebecca E.
Dwivedi, Bhakti
Arthur, Robert A.
Dinasarapu, Ashok Reddy
Johnston, H. Richard
Claussen, Henry
Tucker-Burden, Carol
Ramalingam, Suresh S.
Fu, Haian
Zhou, Wei
Marcus, Adam I.
Gilbert-Ross, Melissa
author_facet Koo, Junghui
Seong, Chang-Soo
Parker, Rebecca E.
Dwivedi, Bhakti
Arthur, Robert A.
Dinasarapu, Ashok Reddy
Johnston, H. Richard
Claussen, Henry
Tucker-Burden, Carol
Ramalingam, Suresh S.
Fu, Haian
Zhou, Wei
Marcus, Adam I.
Gilbert-Ross, Melissa
author_sort Koo, Junghui
collection PubMed
description The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that likely contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical discovery strategies designed to exploit invasive phenotypes are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early invasion phenotypes in the two most prominent molecular subtypes, TP53 and LKB1, of KRAS-driven lung adenocarcinoma (LUAD). By combining live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix with RNA transcriptome profiling, we identified the LKB1-specific upregulation of bone morphogenetic protein 6 (BMP6). Examination of early-stage lung cancer patients confirmed upregulation of BMP6 in LKB1-mutant lung tumors. At the molecular level, we find that the canonical iron regulatory hormone Hepcidin is induced via BMP6 signaling upon LKB1 loss, where intact LKB1 kinase activity is necessary to maintain signaling homeostasis. Furthermore, pre-clinical studies in a novel Kras/Lkb1-mutant syngeneic mouse model show that potent growth suppression was achieved by inhibiting the ALK2/BMP6 signaling axis with single agents that are currently in clinical trials. We show that alterations in the iron homeostasis pathway are accompanied by simultaneous upregulation of ferroptosis protection proteins. Thus, LKB1 is sufficient to regulate both the ‘gas’ and ‘breaks’ to finely tune iron-regulated tumor progression.
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spelling pubmed-103126892023-07-01 Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer Koo, Junghui Seong, Chang-Soo Parker, Rebecca E. Dwivedi, Bhakti Arthur, Robert A. Dinasarapu, Ashok Reddy Johnston, H. Richard Claussen, Henry Tucker-Burden, Carol Ramalingam, Suresh S. Fu, Haian Zhou, Wei Marcus, Adam I. Gilbert-Ross, Melissa bioRxiv Article The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that likely contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical discovery strategies designed to exploit invasive phenotypes are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early invasion phenotypes in the two most prominent molecular subtypes, TP53 and LKB1, of KRAS-driven lung adenocarcinoma (LUAD). By combining live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix with RNA transcriptome profiling, we identified the LKB1-specific upregulation of bone morphogenetic protein 6 (BMP6). Examination of early-stage lung cancer patients confirmed upregulation of BMP6 in LKB1-mutant lung tumors. At the molecular level, we find that the canonical iron regulatory hormone Hepcidin is induced via BMP6 signaling upon LKB1 loss, where intact LKB1 kinase activity is necessary to maintain signaling homeostasis. Furthermore, pre-clinical studies in a novel Kras/Lkb1-mutant syngeneic mouse model show that potent growth suppression was achieved by inhibiting the ALK2/BMP6 signaling axis with single agents that are currently in clinical trials. We show that alterations in the iron homeostasis pathway are accompanied by simultaneous upregulation of ferroptosis protection proteins. Thus, LKB1 is sufficient to regulate both the ‘gas’ and ‘breaks’ to finely tune iron-regulated tumor progression. Cold Spring Harbor Laboratory 2023-06-14 /pmc/articles/PMC10312689/ /pubmed/37398244 http://dx.doi.org/10.1101/2023.06.14.544941 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Koo, Junghui
Seong, Chang-Soo
Parker, Rebecca E.
Dwivedi, Bhakti
Arthur, Robert A.
Dinasarapu, Ashok Reddy
Johnston, H. Richard
Claussen, Henry
Tucker-Burden, Carol
Ramalingam, Suresh S.
Fu, Haian
Zhou, Wei
Marcus, Adam I.
Gilbert-Ross, Melissa
Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer
title Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer
title_full Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer
title_fullStr Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer
title_full_unstemmed Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer
title_short Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer
title_sort live-cell invasive phenotyping uncovers the alk2/bmp6 iron homeostasis pathway as a therapeutic vulnerability in lkb1-mutant lung cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312689/
https://www.ncbi.nlm.nih.gov/pubmed/37398244
http://dx.doi.org/10.1101/2023.06.14.544941
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