Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype

Abstract Polo-like kinase 4 (Plk4), the major regulator of centriole biogenesis, has emerged as a putative therapeutic target in cancer due to its abnormal expression in human carcinomas, leading to centrosome number deregulation, mitotic defects and chromosomal instability. Moreover, Plk4 deregulat...

Full description

Bibliographic Details
Main Authors: Irina Fonseca, Cíntia Horta, Ana Sofia Ribeiro, Barbara Sousa, Gaëlle Marteil, Mónica Bettencourt-Dias, Joana Paredes
Format: Article
Language:English
Published: Nature Publishing Group 2023-02-01
Series:Cell Death and Disease
Online Access:https://doi.org/10.1038/s41419-023-05618-1
_version_ 1797863373169229824
author Irina Fonseca
Cíntia Horta
Ana Sofia Ribeiro
Barbara Sousa
Gaëlle Marteil
Mónica Bettencourt-Dias
Joana Paredes
author_facet Irina Fonseca
Cíntia Horta
Ana Sofia Ribeiro
Barbara Sousa
Gaëlle Marteil
Mónica Bettencourt-Dias
Joana Paredes
author_sort Irina Fonseca
collection DOAJ
description Abstract Polo-like kinase 4 (Plk4), the major regulator of centriole biogenesis, has emerged as a putative therapeutic target in cancer due to its abnormal expression in human carcinomas, leading to centrosome number deregulation, mitotic defects and chromosomal instability. Moreover, Plk4 deregulation promotes tumor growth and metastasis in mouse models and is significantly associated with poor patient prognosis. Here, we further investigate the role of Plk4 in carcinogenesis and show that its overexpression significantly potentiates resistance to cell death by anoikis of nontumorigenic p53 knock-out (p53KO) mammary epithelial cells. Importantly, this effect is independent of Plk4’s role in centrosome biogenesis, suggesting that this kinase has additional cellular functions. Interestingly, the Plk4-induced anoikis resistance is associated with the induction of a stable hybrid epithelial-mesenchymal phenotype and is partially dependent on P-cadherin upregulation. Furthermore, we found that the conditioned media of Plk4-induced p53KO mammary epithelial cells also induces anoikis resistance of breast cancer cells in a paracrine way, being also partially dependent on soluble P-cadherin secretion. Our work shows, for the first time, that high expression levels of Plk4 induce anoikis resistance of both mammary epithelial cells with p53KO background, as well as of breast cancer cells exposed to their secretome, which is partially mediated through P-cadherin upregulation. These results reinforce the idea that Plk4, independently of its role in centrosome biogenesis, functions as an oncogene, by impacting the tumor microenvironment to promote malignancy.
first_indexed 2024-04-09T22:34:32Z
format Article
id doaj.art-0219254cd3364235a1c703b0b1589e7c
institution Directory Open Access Journal
issn 2041-4889
language English
last_indexed 2024-04-09T22:34:32Z
publishDate 2023-02-01
publisher Nature Publishing Group
record_format Article
series Cell Death and Disease
spelling doaj.art-0219254cd3364235a1c703b0b1589e7c2023-03-22T12:32:52ZengNature Publishing GroupCell Death and Disease2041-48892023-02-0114211210.1038/s41419-023-05618-1Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotypeIrina Fonseca0Cíntia Horta1Ana Sofia Ribeiro2Barbara Sousa3Gaëlle Marteil4Mónica Bettencourt-Dias5Joana Paredes6Instituto Gulbenkian de Ciência (IGC)Instituto Gulbenkian de Ciência (IGC)Instituto de Investigação e Inovação em Saúde (i3S)Instituto de Investigação e Inovação em Saúde (i3S)IMoST UMR 1240 INSERM/UCAInstituto Gulbenkian de Ciência (IGC)Instituto de Investigação e Inovação em Saúde (i3S)Abstract Polo-like kinase 4 (Plk4), the major regulator of centriole biogenesis, has emerged as a putative therapeutic target in cancer due to its abnormal expression in human carcinomas, leading to centrosome number deregulation, mitotic defects and chromosomal instability. Moreover, Plk4 deregulation promotes tumor growth and metastasis in mouse models and is significantly associated with poor patient prognosis. Here, we further investigate the role of Plk4 in carcinogenesis and show that its overexpression significantly potentiates resistance to cell death by anoikis of nontumorigenic p53 knock-out (p53KO) mammary epithelial cells. Importantly, this effect is independent of Plk4’s role in centrosome biogenesis, suggesting that this kinase has additional cellular functions. Interestingly, the Plk4-induced anoikis resistance is associated with the induction of a stable hybrid epithelial-mesenchymal phenotype and is partially dependent on P-cadherin upregulation. Furthermore, we found that the conditioned media of Plk4-induced p53KO mammary epithelial cells also induces anoikis resistance of breast cancer cells in a paracrine way, being also partially dependent on soluble P-cadherin secretion. Our work shows, for the first time, that high expression levels of Plk4 induce anoikis resistance of both mammary epithelial cells with p53KO background, as well as of breast cancer cells exposed to their secretome, which is partially mediated through P-cadherin upregulation. These results reinforce the idea that Plk4, independently of its role in centrosome biogenesis, functions as an oncogene, by impacting the tumor microenvironment to promote malignancy.https://doi.org/10.1038/s41419-023-05618-1
spellingShingle Irina Fonseca
Cíntia Horta
Ana Sofia Ribeiro
Barbara Sousa
Gaëlle Marteil
Mónica Bettencourt-Dias
Joana Paredes
Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype
Cell Death and Disease
title Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype
title_full Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype
title_fullStr Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype
title_full_unstemmed Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype
title_short Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype
title_sort polo like kinase 4 plk4 potentiates anoikis resistance of p53ko mammary epithelial cells by inducing a hybrid emt phenotype
url https://doi.org/10.1038/s41419-023-05618-1
work_keys_str_mv AT irinafonseca pololikekinase4plk4potentiatesanoikisresistanceofp53komammaryepithelialcellsbyinducingahybridemtphenotype
AT cintiahorta pololikekinase4plk4potentiatesanoikisresistanceofp53komammaryepithelialcellsbyinducingahybridemtphenotype
AT anasofiaribeiro pololikekinase4plk4potentiatesanoikisresistanceofp53komammaryepithelialcellsbyinducingahybridemtphenotype
AT barbarasousa pololikekinase4plk4potentiatesanoikisresistanceofp53komammaryepithelialcellsbyinducingahybridemtphenotype
AT gaellemarteil pololikekinase4plk4potentiatesanoikisresistanceofp53komammaryepithelialcellsbyinducingahybridemtphenotype
AT monicabettencourtdias pololikekinase4plk4potentiatesanoikisresistanceofp53komammaryepithelialcellsbyinducingahybridemtphenotype
AT joanaparedes pololikekinase4plk4potentiatesanoikisresistanceofp53komammaryepithelialcellsbyinducingahybridemtphenotype