Physical confinement promotes mesenchymal trans-differentiation of invading transformed cells in vivo

Teresa Zulueta-Coarasa; John Fadul; Marjana Ahmed; Jody Rosenblatt

doi:10.1016/j.isci.2022.105330

Physical confinement promotes mesenchymal trans-differentiation of invading transformed cells in vivo

Teresa Zulueta-Coarasa, John Fadul, Marjana Ahmed, Jody Rosenblatt^*

^*Corresponding author for this work

Randall Centre of Cell & Molecular Biophysics

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Metastasis is tightly linked with poor cancer prognosis, yet it is not clear how transformed cells become invasive carcinomas. We previously discovered that single KRas^V12-transformed cells can invade directly from the epithelium by basal cell extrusion. During this process, cells de-differentiate by mechanically pinching off their epithelial determinants, but how they trans-differentiate into a migratory, mesenchymal phenotype is not known. Here, we demonstrate that basally extruded KRas^V12-expressing cells become significantly deformed as they invade the zebrafish body. Decreasing the confinement that cells experience after they invade reduces the percentage of KRas^V12 cells that trans-differentiate into mesenchymal cell types, while higher confinement increases this percentage. Additionally, increased confinement promotes accumulation of internal masses over time. Altogether, our results suggest that mechanical forces drive not only de-differentiation of KRas^V12-transformed epithelial cells as they invade but also their re-differentiation into mesenchymal phenotypes that contribute to distant metastases.

Original language	English
Article number	105330
Journal	iScience
Volume	25
Issue number	11
DOIs	https://doi.org/10.1016/j.isci.2022.105330
Publication status	Published - 18 Nov 2022

Keywords

Cancer
Cell biology
Organizational aspects of cell biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2022.105330

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@article{ef72baf072c7409e8857090c38d5af7c,

title = "Physical confinement promotes mesenchymal trans-differentiation of invading transformed cells in vivo",

abstract = "Metastasis is tightly linked with poor cancer prognosis, yet it is not clear how transformed cells become invasive carcinomas. We previously discovered that single KRasV12-transformed cells can invade directly from the epithelium by basal cell extrusion. During this process, cells de-differentiate by mechanically pinching off their epithelial determinants, but how they trans-differentiate into a migratory, mesenchymal phenotype is not known. Here, we demonstrate that basally extruded KRasV12-expressing cells become significantly deformed as they invade the zebrafish body. Decreasing the confinement that cells experience after they invade reduces the percentage of KRasV12 cells that trans-differentiate into mesenchymal cell types, while higher confinement increases this percentage. Additionally, increased confinement promotes accumulation of internal masses over time. Altogether, our results suggest that mechanical forces drive not only de-differentiation of KRasV12-transformed epithelial cells as they invade but also their re-differentiation into mesenchymal phenotypes that contribute to distant metastases.",

keywords = "Cancer, Cell biology, Organizational aspects of cell biology",

author = "Teresa Zulueta-Coarasa and John Fadul and Marjana Ahmed and Jody Rosenblatt",

note = "Funding Information: We are grateful to Jon Clarke for sharing the lamc1 morpholino and the Tg(actb1:mCherry–utrCH) and lamc1 sa379 lines with us, to Simon Hughes for sharing the Tg(bAct:hRas-eGFP) line, and to Claudia Linker for the H2B-RFP mRNA. We thank Claudia Linker and the Rosenblatt lab for useful discussions and Rachel Moore for technical help. We are grateful to Alberto Elosegui-Artola and Rachel Moore for comments on the manuscript. T.Z.-C. was supported by an EMBO Long-Term Fellowship ( ALTF 1130-2018 ), and the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 840767 . This work was supported by a Cancer Research UK Programme Grant ( DRCNPG-May21\100007 ), an Academy of Medical Sciences Professorship APR2-1007-2 , a National Institute of Health R01GM102169 , and a Howard Hughes Faculty Scholar Award 55108560 to J.R. Funding Information: We are grateful to Jon Clarke for sharing the lamc1 morpholino and the Tg(actb1:mCherry–utrCH) and lamc1sa379 lines with us, to Simon Hughes for sharing the Tg(bAct:hRas-eGFP) line, and to Claudia Linker for the H2B-RFP mRNA. We thank Claudia Linker and the Rosenblatt lab for useful discussions and Rachel Moore for technical help. We are grateful to Alberto Elosegui-Artola and Rachel Moore for comments on the manuscript. T.Z.-C. was supported by an EMBO Long-Term Fellowship (ALTF 1130-2018), and the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 840767. This work was supported by a Cancer Research UK Programme Grant (DRCNPG-May21\100007), an Academy of Medical Sciences Professorship APR2-1007-2, a National Institute of Health R01GM102169, and a Howard Hughes Faculty Scholar Award 55108560 to J.R. J.R. and T.Z.-C. designed experiments, interpreted data, and co-wrote the manuscript. T.Z.-C. performed all experiments and quantified most data. J.F. made zebrafish Tol2 constructs and provided technical assistance, critical interpretation of data and comments on the manuscript. M.A. quantified the percentage of neuron-like cells in controls and lamc1 mutans, and the size of zebrafish embedded in 0% and 2% agarose. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = nov,

day = "18",

doi = "10.1016/j.isci.2022.105330",

language = "English",

volume = "25",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier publishing company",

number = "11",

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TY - JOUR

T1 - Physical confinement promotes mesenchymal trans-differentiation of invading transformed cells in vivo

AU - Zulueta-Coarasa, Teresa

AU - Fadul, John

AU - Ahmed, Marjana

AU - Rosenblatt, Jody

N1 - Funding Information: We are grateful to Jon Clarke for sharing the lamc1 morpholino and the Tg(actb1:mCherry–utrCH) and lamc1 sa379 lines with us, to Simon Hughes for sharing the Tg(bAct:hRas-eGFP) line, and to Claudia Linker for the H2B-RFP mRNA. We thank Claudia Linker and the Rosenblatt lab for useful discussions and Rachel Moore for technical help. We are grateful to Alberto Elosegui-Artola and Rachel Moore for comments on the manuscript. T.Z.-C. was supported by an EMBO Long-Term Fellowship ( ALTF 1130-2018 ), and the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 840767 . This work was supported by a Cancer Research UK Programme Grant ( DRCNPG-May21\100007 ), an Academy of Medical Sciences Professorship APR2-1007-2 , a National Institute of Health R01GM102169 , and a Howard Hughes Faculty Scholar Award 55108560 to J.R. Funding Information: We are grateful to Jon Clarke for sharing the lamc1 morpholino and the Tg(actb1:mCherry–utrCH) and lamc1sa379 lines with us, to Simon Hughes for sharing the Tg(bAct:hRas-eGFP) line, and to Claudia Linker for the H2B-RFP mRNA. We thank Claudia Linker and the Rosenblatt lab for useful discussions and Rachel Moore for technical help. We are grateful to Alberto Elosegui-Artola and Rachel Moore for comments on the manuscript. T.Z.-C. was supported by an EMBO Long-Term Fellowship (ALTF 1130-2018), and the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 840767. This work was supported by a Cancer Research UK Programme Grant (DRCNPG-May21\100007), an Academy of Medical Sciences Professorship APR2-1007-2, a National Institute of Health R01GM102169, and a Howard Hughes Faculty Scholar Award 55108560 to J.R. J.R. and T.Z.-C. designed experiments, interpreted data, and co-wrote the manuscript. T.Z.-C. performed all experiments and quantified most data. J.F. made zebrafish Tol2 constructs and provided technical assistance, critical interpretation of data and comments on the manuscript. M.A. quantified the percentage of neuron-like cells in controls and lamc1 mutans, and the size of zebrafish embedded in 0% and 2% agarose. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. Publisher Copyright: © 2022 The Authors

PY - 2022/11/18

Y1 - 2022/11/18

N2 - Metastasis is tightly linked with poor cancer prognosis, yet it is not clear how transformed cells become invasive carcinomas. We previously discovered that single KRasV12-transformed cells can invade directly from the epithelium by basal cell extrusion. During this process, cells de-differentiate by mechanically pinching off their epithelial determinants, but how they trans-differentiate into a migratory, mesenchymal phenotype is not known. Here, we demonstrate that basally extruded KRasV12-expressing cells become significantly deformed as they invade the zebrafish body. Decreasing the confinement that cells experience after they invade reduces the percentage of KRasV12 cells that trans-differentiate into mesenchymal cell types, while higher confinement increases this percentage. Additionally, increased confinement promotes accumulation of internal masses over time. Altogether, our results suggest that mechanical forces drive not only de-differentiation of KRasV12-transformed epithelial cells as they invade but also their re-differentiation into mesenchymal phenotypes that contribute to distant metastases.

AB - Metastasis is tightly linked with poor cancer prognosis, yet it is not clear how transformed cells become invasive carcinomas. We previously discovered that single KRasV12-transformed cells can invade directly from the epithelium by basal cell extrusion. During this process, cells de-differentiate by mechanically pinching off their epithelial determinants, but how they trans-differentiate into a migratory, mesenchymal phenotype is not known. Here, we demonstrate that basally extruded KRasV12-expressing cells become significantly deformed as they invade the zebrafish body. Decreasing the confinement that cells experience after they invade reduces the percentage of KRasV12 cells that trans-differentiate into mesenchymal cell types, while higher confinement increases this percentage. Additionally, increased confinement promotes accumulation of internal masses over time. Altogether, our results suggest that mechanical forces drive not only de-differentiation of KRasV12-transformed epithelial cells as they invade but also their re-differentiation into mesenchymal phenotypes that contribute to distant metastases.

KW - Cancer

KW - Cell biology

KW - Organizational aspects of cell biology

UR - http://www.scopus.com/inward/record.url?scp=85140388123&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2022.105330

DO - 10.1016/j.isci.2022.105330

M3 - Article

AN - SCOPUS:85140388123

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 11

M1 - 105330

ER -

Physical confinement promotes mesenchymal trans-differentiation of invading transformed cells in vivo

Abstract

Keywords

UN SDGs

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