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Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence

Cancer cells encounter a hostile tumor microenvironment (TME), and their adaptations to metabolic stresses determine metastatic competence. Here, we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) is induced in hypoxic tumors acquiring metabolic plastici...

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Autores principales: Dai, Tao, Rosario, Spencer R., Katsuta, Eriko, Dessai, Abhisha Sawant, Paterson, Emily J., Novickis, Aaron T., Cortes Gomez, Eduardo, Zhu, Bokai, Liu, Song, Wang, Hai, Abrams, Scott I., Seshadri, Mukund, Bshara, Wiam, Dasgupta, Subhamoy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9807018/
https://www.ncbi.nlm.nih.gov/pubmed/36476868
http://dx.doi.org/10.1016/j.celrep.2022.111756
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author Dai, Tao
Rosario, Spencer R.
Katsuta, Eriko
Dessai, Abhisha Sawant
Paterson, Emily J.
Novickis, Aaron T.
Cortes Gomez, Eduardo
Zhu, Bokai
Liu, Song
Wang, Hai
Abrams, Scott I.
Seshadri, Mukund
Bshara, Wiam
Dasgupta, Subhamoy
author_facet Dai, Tao
Rosario, Spencer R.
Katsuta, Eriko
Dessai, Abhisha Sawant
Paterson, Emily J.
Novickis, Aaron T.
Cortes Gomez, Eduardo
Zhu, Bokai
Liu, Song
Wang, Hai
Abrams, Scott I.
Seshadri, Mukund
Bshara, Wiam
Dasgupta, Subhamoy
author_sort Dai, Tao
collection PubMed
description Cancer cells encounter a hostile tumor microenvironment (TME), and their adaptations to metabolic stresses determine metastatic competence. Here, we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) is induced in hypoxic tumors acquiring metabolic plasticity and invasive phenotype. In mouse models of breast cancer, genetic ablation of PFKFB4 significantly delays distant organ metastasis, reducing local lymph node invasion by suppressing expression of invasive gene signature including integrin β3. Photoacoustic imaging followed by metabolomics analyses of hypoxic tumors show that PFKFB4 drives metabolic flexibility, enabling rapid detoxification of reactive oxygen species favoring survival under selective pressure. Mechanistically, hypoxic induction triggers nuclear translocation of PFKFB4 accentuating non-canonical transcriptional activation of HIF-1α, and breast cancer patients with increased nuclear PFKFB4 in their tumors are found to be significantly associated with poor prognosis. Our findings imply that PFKFB4 induction is crucial for tumor cell adaptation in the hypoxic TME that determines metastatic competence.
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spelling pubmed-98070182023-01-02 Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence Dai, Tao Rosario, Spencer R. Katsuta, Eriko Dessai, Abhisha Sawant Paterson, Emily J. Novickis, Aaron T. Cortes Gomez, Eduardo Zhu, Bokai Liu, Song Wang, Hai Abrams, Scott I. Seshadri, Mukund Bshara, Wiam Dasgupta, Subhamoy Cell Rep Article Cancer cells encounter a hostile tumor microenvironment (TME), and their adaptations to metabolic stresses determine metastatic competence. Here, we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) is induced in hypoxic tumors acquiring metabolic plasticity and invasive phenotype. In mouse models of breast cancer, genetic ablation of PFKFB4 significantly delays distant organ metastasis, reducing local lymph node invasion by suppressing expression of invasive gene signature including integrin β3. Photoacoustic imaging followed by metabolomics analyses of hypoxic tumors show that PFKFB4 drives metabolic flexibility, enabling rapid detoxification of reactive oxygen species favoring survival under selective pressure. Mechanistically, hypoxic induction triggers nuclear translocation of PFKFB4 accentuating non-canonical transcriptional activation of HIF-1α, and breast cancer patients with increased nuclear PFKFB4 in their tumors are found to be significantly associated with poor prognosis. Our findings imply that PFKFB4 induction is crucial for tumor cell adaptation in the hypoxic TME that determines metastatic competence. 2022-12-06 /pmc/articles/PMC9807018/ /pubmed/36476868 http://dx.doi.org/10.1016/j.celrep.2022.111756 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Dai, Tao
Rosario, Spencer R.
Katsuta, Eriko
Dessai, Abhisha Sawant
Paterson, Emily J.
Novickis, Aaron T.
Cortes Gomez, Eduardo
Zhu, Bokai
Liu, Song
Wang, Hai
Abrams, Scott I.
Seshadri, Mukund
Bshara, Wiam
Dasgupta, Subhamoy
Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence
title Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence
title_full Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence
title_fullStr Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence
title_full_unstemmed Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence
title_short Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence
title_sort hypoxic activation of pfkfb4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9807018/
https://www.ncbi.nlm.nih.gov/pubmed/36476868
http://dx.doi.org/10.1016/j.celrep.2022.111756
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