Fine-tuning the metabolic rewiring and adaptation of translational machinery during an epithelial-mesenchymal transition in breast cancer cells

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Fine-tuning the metabolic rewiring and adaptation of translational machinery during an epithelial-mesenchymal transition in breast cancer cells. / Fernández-Calero, Tamara; Davyt, Marcos; Perelmuter, Karen; Chalar, Cora; Bampi, Giovana; Persson, Helena; Tosar, Juan Pablo; Hafstað, Völundur; Naya, Hugo; Rovira, Carlos; Bollati-Fogolín, Mariela; Ehrlich, Ricardo; Flouriot, Gilles; Ignatova, Zoya; Marín, Mónica.

In: Cancer & Metabolism, Vol. 8, 2020, p. 8.

Research output: Contribution to journalArticle

Harvard

Fernández-Calero, T, Davyt, M, Perelmuter, K, Chalar, C, Bampi, G, Persson, H, Tosar, JP, Hafstað, V, Naya, H, Rovira, C, Bollati-Fogolín, M, Ehrlich, R, Flouriot, G, Ignatova, Z & Marín, M 2020, 'Fine-tuning the metabolic rewiring and adaptation of translational machinery during an epithelial-mesenchymal transition in breast cancer cells', Cancer & Metabolism, vol. 8, pp. 8. https://doi.org/10.1186/s40170-020-00216-7

APA

Fernández-Calero, T., Davyt, M., Perelmuter, K., Chalar, C., Bampi, G., Persson, H., Tosar, J. P., Hafstað, V., Naya, H., Rovira, C., Bollati-Fogolín, M., Ehrlich, R., Flouriot, G., Ignatova, Z., & Marín, M. (2020). Fine-tuning the metabolic rewiring and adaptation of translational machinery during an epithelial-mesenchymal transition in breast cancer cells. Cancer & Metabolism, 8, 8. https://doi.org/10.1186/s40170-020-00216-7

CBE

Fernández-Calero T, Davyt M, Perelmuter K, Chalar C, Bampi G, Persson H, Tosar JP, Hafstað V, Naya H, Rovira C, Bollati-Fogolín M, Ehrlich R, Flouriot G, Ignatova Z, Marín M. 2020. Fine-tuning the metabolic rewiring and adaptation of translational machinery during an epithelial-mesenchymal transition in breast cancer cells. Cancer & Metabolism. 8:8. https://doi.org/10.1186/s40170-020-00216-7

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Fernández-Calero, Tamara ; Davyt, Marcos ; Perelmuter, Karen ; Chalar, Cora ; Bampi, Giovana ; Persson, Helena ; Tosar, Juan Pablo ; Hafstað, Völundur ; Naya, Hugo ; Rovira, Carlos ; Bollati-Fogolín, Mariela ; Ehrlich, Ricardo ; Flouriot, Gilles ; Ignatova, Zoya ; Marín, Mónica. / Fine-tuning the metabolic rewiring and adaptation of translational machinery during an epithelial-mesenchymal transition in breast cancer cells. In: Cancer & Metabolism. 2020 ; Vol. 8. pp. 8.

RIS

TY - JOUR

T1 - Fine-tuning the metabolic rewiring and adaptation of translational machinery during an epithelial-mesenchymal transition in breast cancer cells

AU - Fernández-Calero, Tamara

AU - Davyt, Marcos

AU - Perelmuter, Karen

AU - Chalar, Cora

AU - Bampi, Giovana

AU - Persson, Helena

AU - Tosar, Juan Pablo

AU - Hafstað, Völundur

AU - Naya, Hugo

AU - Rovira, Carlos

AU - Bollati-Fogolín, Mariela

AU - Ehrlich, Ricardo

AU - Flouriot, Gilles

AU - Ignatova, Zoya

AU - Marín, Mónica

N1 - © The Author(s) 2020. Tamara Fernández-Calero and Marcos Davyt contributed equally to this work.

PY - 2020

Y1 - 2020

N2 - Abstract: Background: During breast cancer progression, the epithelial to mesenchymal transition has been associated with metastasis and endocrine therapy resistance; however, the underlying mechanisms remain elusive. To gain insight into this process, we studied the transition undergone by MCF7-derived cells, which is driven by the constitutive nuclear expression of a MKL1 variant devoid of the actin-binding domain (MKL1 ΔN200). We characterized the adaptive changes that occur during the MKL1-induced cellular model and focused on regulation of translation machinery and metabolic adaptation.Methods: We performed a genome-wide analysis at the transcriptional and translational level using ribosome profiling complemented with RNA-Seq and analyzed the expression of components of the translation machinery and enzymes involved in energy metabolism. NGS data were correlated with metabolomic measurements and quantification of specific mRNAs extracted from polysomes and western blots.Results: Our results reveal the expression profiles of a luminal to basal-like state in accordance with an epithelial to mesenchymal transition. During the transition, the synthesis of ribosomal proteins and that of many translational factors was upregulated. This overexpression of the translational machinery appears to be regulated at the translational level. Our results indicate an increase of ribosome biogenesis and translation activity. We detected an extensive metabolic rewiring occurring in an already "Warburg-like" context, in which enzyme isoform switches and metabolic shunts indicate a crucial role of HIF-1α along with other master regulatory factors. Furthermore, we detected a decrease in the expression of enzymes involved in ribonucleotide synthesis from the pentose phosphate pathway. During this transition, cells increase in size, downregulate genes associated with proliferation, and strongly upregulate expression of cytoskeletal and extracellular matrix genes.Conclusions: Our study reveals multiple regulatory events associated with metabolic and translational machinery adaptation during an epithelial mesenchymal-like transition process. During this major cellular transition, cells achieve a new homeostatic state ensuring their survival. This work shows that ribosome profiling complemented with RNA-Seq is a powerful approach to unveil in-depth global adaptive cellular responses and the interconnection among regulatory circuits, which will be helpful for identification of new therapeutic targets.

AB - Abstract: Background: During breast cancer progression, the epithelial to mesenchymal transition has been associated with metastasis and endocrine therapy resistance; however, the underlying mechanisms remain elusive. To gain insight into this process, we studied the transition undergone by MCF7-derived cells, which is driven by the constitutive nuclear expression of a MKL1 variant devoid of the actin-binding domain (MKL1 ΔN200). We characterized the adaptive changes that occur during the MKL1-induced cellular model and focused on regulation of translation machinery and metabolic adaptation.Methods: We performed a genome-wide analysis at the transcriptional and translational level using ribosome profiling complemented with RNA-Seq and analyzed the expression of components of the translation machinery and enzymes involved in energy metabolism. NGS data were correlated with metabolomic measurements and quantification of specific mRNAs extracted from polysomes and western blots.Results: Our results reveal the expression profiles of a luminal to basal-like state in accordance with an epithelial to mesenchymal transition. During the transition, the synthesis of ribosomal proteins and that of many translational factors was upregulated. This overexpression of the translational machinery appears to be regulated at the translational level. Our results indicate an increase of ribosome biogenesis and translation activity. We detected an extensive metabolic rewiring occurring in an already "Warburg-like" context, in which enzyme isoform switches and metabolic shunts indicate a crucial role of HIF-1α along with other master regulatory factors. Furthermore, we detected a decrease in the expression of enzymes involved in ribonucleotide synthesis from the pentose phosphate pathway. During this transition, cells increase in size, downregulate genes associated with proliferation, and strongly upregulate expression of cytoskeletal and extracellular matrix genes.Conclusions: Our study reveals multiple regulatory events associated with metabolic and translational machinery adaptation during an epithelial mesenchymal-like transition process. During this major cellular transition, cells achieve a new homeostatic state ensuring their survival. This work shows that ribosome profiling complemented with RNA-Seq is a powerful approach to unveil in-depth global adaptive cellular responses and the interconnection among regulatory circuits, which will be helpful for identification of new therapeutic targets.

U2 - 10.1186/s40170-020-00216-7

DO - 10.1186/s40170-020-00216-7

M3 - Article

C2 - 32699630

VL - 8

SP - 8

JO - Cancer & Metabolism

JF - Cancer & Metabolism

SN - 2049-3002

ER -