Cargando…

Selection of established tumour cells through narrow diameter micropores enriches for elevated Ras/Raf/MEK/ERK MAPK signalling and enhanced tumour growth

As normal cells become cancer cells, and progress towards malignancy, they become progressively softer. Advantages of this change are that tumour cells become more deformable, and better able to move through narrow constraints. We designed a positive selection strategy that enriched for cells which...

Descripción completa

Detalles Bibliográficos
Autores principales: Rudzka, Dominika a, Mason, Susan, Neilson, Matthew, McGarry, Lynn, Kalna, Gabriela, Hedley, Ann, Blyth, Karen, Olson, Michael F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204978/
https://www.ncbi.nlm.nih.gov/pubmed/32569510
http://dx.doi.org/10.1080/21541248.2020.1780108
_version_ 1783708418921463808
author Rudzka, Dominika a
Mason, Susan
Neilson, Matthew
McGarry, Lynn
Kalna, Gabriela
Hedley, Ann
Blyth, Karen
Olson, Michael F.
author_facet Rudzka, Dominika a
Mason, Susan
Neilson, Matthew
McGarry, Lynn
Kalna, Gabriela
Hedley, Ann
Blyth, Karen
Olson, Michael F.
author_sort Rudzka, Dominika a
collection PubMed
description As normal cells become cancer cells, and progress towards malignancy, they become progressively softer. Advantages of this change are that tumour cells become more deformable, and better able to move through narrow constraints. We designed a positive selection strategy that enriched for cells which could move through narrow diameter micropores to identify cell phenotypes that enabled constrained migration. Using human MDA MB 231 breast cancer and MDA MB 435 melanoma cancer cells, we found that micropore selection favoured cells with relatively higher Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signalling, which affected actin cytoskeleton organization, focal adhesion density and cell elasticity. In this follow-up study, we provide further evidence that selection through micropores enriched for cells with altered cell morphology and adhesion. Additional analysis of RNA sequencing data revealed a set of transcripts associated with small cell size that was independent of constrained migration. Gene set enrichment analysis identified the ‘matrisome’ as the most significantly altered gene set linked with small size. When grown as orthotopic xenograft tumours in immunocompromised mice, micropore selected cells grew significantly faster than Parent or Flow-Sorted cells. Using mathematical modelling, we determined that there is an interaction between 1) the cell to gap size ratio; 2) the bending rigidity of the cell, which enable movement through narrow gaps. These results extend our previous conclusion that Ras/Raf/MEK/ERK MAPK signalling has a significant role in regulating cell biomechanics by showing that the selective pressure of movement through narrow gaps also enriches for increased tumour growth in vivo.
format Online
Article
Text
id pubmed-8204978
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Taylor & Francis
record_format MEDLINE/PubMed
spelling pubmed-82049782021-06-24 Selection of established tumour cells through narrow diameter micropores enriches for elevated Ras/Raf/MEK/ERK MAPK signalling and enhanced tumour growth Rudzka, Dominika a Mason, Susan Neilson, Matthew McGarry, Lynn Kalna, Gabriela Hedley, Ann Blyth, Karen Olson, Michael F. Small GTPases Research Paper As normal cells become cancer cells, and progress towards malignancy, they become progressively softer. Advantages of this change are that tumour cells become more deformable, and better able to move through narrow constraints. We designed a positive selection strategy that enriched for cells which could move through narrow diameter micropores to identify cell phenotypes that enabled constrained migration. Using human MDA MB 231 breast cancer and MDA MB 435 melanoma cancer cells, we found that micropore selection favoured cells with relatively higher Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signalling, which affected actin cytoskeleton organization, focal adhesion density and cell elasticity. In this follow-up study, we provide further evidence that selection through micropores enriched for cells with altered cell morphology and adhesion. Additional analysis of RNA sequencing data revealed a set of transcripts associated with small cell size that was independent of constrained migration. Gene set enrichment analysis identified the ‘matrisome’ as the most significantly altered gene set linked with small size. When grown as orthotopic xenograft tumours in immunocompromised mice, micropore selected cells grew significantly faster than Parent or Flow-Sorted cells. Using mathematical modelling, we determined that there is an interaction between 1) the cell to gap size ratio; 2) the bending rigidity of the cell, which enable movement through narrow gaps. These results extend our previous conclusion that Ras/Raf/MEK/ERK MAPK signalling has a significant role in regulating cell biomechanics by showing that the selective pressure of movement through narrow gaps also enriches for increased tumour growth in vivo. Taylor & Francis 2020-06-22 /pmc/articles/PMC8204978/ /pubmed/32569510 http://dx.doi.org/10.1080/21541248.2020.1780108 Text en © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Rudzka, Dominika a
Mason, Susan
Neilson, Matthew
McGarry, Lynn
Kalna, Gabriela
Hedley, Ann
Blyth, Karen
Olson, Michael F.
Selection of established tumour cells through narrow diameter micropores enriches for elevated Ras/Raf/MEK/ERK MAPK signalling and enhanced tumour growth
title Selection of established tumour cells through narrow diameter micropores enriches for elevated Ras/Raf/MEK/ERK MAPK signalling and enhanced tumour growth
title_full Selection of established tumour cells through narrow diameter micropores enriches for elevated Ras/Raf/MEK/ERK MAPK signalling and enhanced tumour growth
title_fullStr Selection of established tumour cells through narrow diameter micropores enriches for elevated Ras/Raf/MEK/ERK MAPK signalling and enhanced tumour growth
title_full_unstemmed Selection of established tumour cells through narrow diameter micropores enriches for elevated Ras/Raf/MEK/ERK MAPK signalling and enhanced tumour growth
title_short Selection of established tumour cells through narrow diameter micropores enriches for elevated Ras/Raf/MEK/ERK MAPK signalling and enhanced tumour growth
title_sort selection of established tumour cells through narrow diameter micropores enriches for elevated ras/raf/mek/erk mapk signalling and enhanced tumour growth
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204978/
https://www.ncbi.nlm.nih.gov/pubmed/32569510
http://dx.doi.org/10.1080/21541248.2020.1780108
work_keys_str_mv AT rudzkadominikaa selectionofestablishedtumourcellsthroughnarrowdiametermicroporesenrichesforelevatedrasrafmekerkmapksignallingandenhancedtumourgrowth
AT masonsusan selectionofestablishedtumourcellsthroughnarrowdiametermicroporesenrichesforelevatedrasrafmekerkmapksignallingandenhancedtumourgrowth
AT neilsonmatthew selectionofestablishedtumourcellsthroughnarrowdiametermicroporesenrichesforelevatedrasrafmekerkmapksignallingandenhancedtumourgrowth
AT mcgarrylynn selectionofestablishedtumourcellsthroughnarrowdiametermicroporesenrichesforelevatedrasrafmekerkmapksignallingandenhancedtumourgrowth
AT kalnagabriela selectionofestablishedtumourcellsthroughnarrowdiametermicroporesenrichesforelevatedrasrafmekerkmapksignallingandenhancedtumourgrowth
AT hedleyann selectionofestablishedtumourcellsthroughnarrowdiametermicroporesenrichesforelevatedrasrafmekerkmapksignallingandenhancedtumourgrowth
AT blythkaren selectionofestablishedtumourcellsthroughnarrowdiametermicroporesenrichesforelevatedrasrafmekerkmapksignallingandenhancedtumourgrowth
AT olsonmichaelf selectionofestablishedtumourcellsthroughnarrowdiametermicroporesenrichesforelevatedrasrafmekerkmapksignallingandenhancedtumourgrowth