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Autophagy Is Polarized toward Cell Front during Migration and Spatially Perturbed by Oncogenic Ras

Autophagy is a physiological degradation process that removes unnecessary or dysfunctional components of cells. It is important for normal cellular homeostasis and as a response to a variety of stresses, such as nutrient deprivation. Defects in autophagy have been linked to numerous human diseases,...

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Autores principales: Singh, Manish Kumar, Zago, Giulia, Veith, Irina, Camonis, Jacques, Coppey, Mathieu, Parrini, Maria Carla
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534269/
https://www.ncbi.nlm.nih.gov/pubmed/34685617
http://dx.doi.org/10.3390/cells10102637
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author Singh, Manish Kumar
Zago, Giulia
Veith, Irina
Camonis, Jacques
Coppey, Mathieu
Parrini, Maria Carla
author_facet Singh, Manish Kumar
Zago, Giulia
Veith, Irina
Camonis, Jacques
Coppey, Mathieu
Parrini, Maria Carla
author_sort Singh, Manish Kumar
collection PubMed
description Autophagy is a physiological degradation process that removes unnecessary or dysfunctional components of cells. It is important for normal cellular homeostasis and as a response to a variety of stresses, such as nutrient deprivation. Defects in autophagy have been linked to numerous human diseases, including cancers. Cancer cells require autophagy to migrate and to invade. Here, we study the intracellular topology of this interplay between autophagy and cell migration by an interdisciplinary live imaging approach which combines micro-patterning techniques and an autophagy reporter (RFP-GFP-LC3) to monitor over time, during directed migration, the back–front spatial distribution of LC3-positive compartments (autophagosomes and autolysosomes). Moreover, by exploiting a genetically controlled cell model, we assessed the impact of transformation by the Ras oncogene, one of the most frequently mutated genes in human cancers, which is known to increase both cell motility and basal autophagy. Static cells displayed an isotropic distribution of autophagy LC3-positive compartments. Directed migration globally increased autophagy and polarized both autophagosomes and autolysosomes at the front of the nucleus of migrating cells. In Ras-transformed cells, the front polarization of LC3 compartments was much less organized, spatially and temporally, as compared to normal cells. This might be a consequence of altered lysosome positioning. In conclusion, this work reveals that autophagy organelles are polarized toward the cell front during migration and that their spatial-temporal dynamics are altered in motile cancer cells that express an oncogenic Ras protein.
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spelling pubmed-85342692021-10-23 Autophagy Is Polarized toward Cell Front during Migration and Spatially Perturbed by Oncogenic Ras Singh, Manish Kumar Zago, Giulia Veith, Irina Camonis, Jacques Coppey, Mathieu Parrini, Maria Carla Cells Article Autophagy is a physiological degradation process that removes unnecessary or dysfunctional components of cells. It is important for normal cellular homeostasis and as a response to a variety of stresses, such as nutrient deprivation. Defects in autophagy have been linked to numerous human diseases, including cancers. Cancer cells require autophagy to migrate and to invade. Here, we study the intracellular topology of this interplay between autophagy and cell migration by an interdisciplinary live imaging approach which combines micro-patterning techniques and an autophagy reporter (RFP-GFP-LC3) to monitor over time, during directed migration, the back–front spatial distribution of LC3-positive compartments (autophagosomes and autolysosomes). Moreover, by exploiting a genetically controlled cell model, we assessed the impact of transformation by the Ras oncogene, one of the most frequently mutated genes in human cancers, which is known to increase both cell motility and basal autophagy. Static cells displayed an isotropic distribution of autophagy LC3-positive compartments. Directed migration globally increased autophagy and polarized both autophagosomes and autolysosomes at the front of the nucleus of migrating cells. In Ras-transformed cells, the front polarization of LC3 compartments was much less organized, spatially and temporally, as compared to normal cells. This might be a consequence of altered lysosome positioning. In conclusion, this work reveals that autophagy organelles are polarized toward the cell front during migration and that their spatial-temporal dynamics are altered in motile cancer cells that express an oncogenic Ras protein. MDPI 2021-10-02 /pmc/articles/PMC8534269/ /pubmed/34685617 http://dx.doi.org/10.3390/cells10102637 Text en © 2021 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
Singh, Manish Kumar
Zago, Giulia
Veith, Irina
Camonis, Jacques
Coppey, Mathieu
Parrini, Maria Carla
Autophagy Is Polarized toward Cell Front during Migration and Spatially Perturbed by Oncogenic Ras
title Autophagy Is Polarized toward Cell Front during Migration and Spatially Perturbed by Oncogenic Ras
title_full Autophagy Is Polarized toward Cell Front during Migration and Spatially Perturbed by Oncogenic Ras
title_fullStr Autophagy Is Polarized toward Cell Front during Migration and Spatially Perturbed by Oncogenic Ras
title_full_unstemmed Autophagy Is Polarized toward Cell Front during Migration and Spatially Perturbed by Oncogenic Ras
title_short Autophagy Is Polarized toward Cell Front during Migration and Spatially Perturbed by Oncogenic Ras
title_sort autophagy is polarized toward cell front during migration and spatially perturbed by oncogenic ras
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534269/
https://www.ncbi.nlm.nih.gov/pubmed/34685617
http://dx.doi.org/10.3390/cells10102637
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