Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis

Antti Arjonen, Riina Kaukonen, Elina Mattila, Pegah Rouhi, Gunilla Högnäs, Harri Sihto, Bryan W. Miller, Jennifer P. Morton, Elmar Bucher, Pekka Taimen, Reetta Virtakoivu, Yihai Cao, Owen J. Sansom, Heikki Joensuu, Johanna Ivaska

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53.driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport ß1 integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53.driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.
Original languageEnglish
Pages (from-to)1069-1082
Number of pages13
JournalJournal of Clinical Investigation
Volume124
Issue number3
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

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Myosins
Up-Regulation
Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Pseudopodia
Integrins
Cell Membrane
Genetic Suppression
Mutation
Pancreatic Neoplasms
Transcriptome
Adenocarcinoma
Cell Line

Cite this

Arjonen, A., Kaukonen, R., Mattila, E., Rouhi, P., Högnäs, G., Sihto, H., ... Ivaska, J. (2014). Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis. Journal of Clinical Investigation, 124(3), 1069-1082. https://doi.org/10.1172/JCI67280
Arjonen, Antti ; Kaukonen, Riina ; Mattila, Elina ; Rouhi, Pegah ; Högnäs, Gunilla ; Sihto, Harri ; Miller, Bryan W. ; Morton, Jennifer P. ; Bucher, Elmar ; Taimen, Pekka ; Virtakoivu, Reetta ; Cao, Yihai ; Sansom, Owen J. ; Joensuu, Heikki ; Ivaska, Johanna. / Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 3. pp. 1069-1082.
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abstract = "Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53.driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport {\ss}1 integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53.driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.",
author = "Antti Arjonen and Riina Kaukonen and Elina Mattila and Pegah Rouhi and Gunilla H{\"o}gn{\"a}s and Harri Sihto and Miller, {Bryan W.} and Morton, {Jennifer P.} and Elmar Bucher and Pekka Taimen and Reetta Virtakoivu and Yihai Cao and Sansom, {Owen J.} and Heikki Joensuu and Johanna Ivaska",
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Arjonen, A, Kaukonen, R, Mattila, E, Rouhi, P, Högnäs, G, Sihto, H, Miller, BW, Morton, JP, Bucher, E, Taimen, P, Virtakoivu, R, Cao, Y, Sansom, OJ, Joensuu, H & Ivaska, J 2014, 'Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis', Journal of Clinical Investigation, vol. 124, no. 3, pp. 1069-1082. https://doi.org/10.1172/JCI67280

Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis. / Arjonen, Antti; Kaukonen, Riina; Mattila, Elina; Rouhi, Pegah; Högnäs, Gunilla; Sihto, Harri; Miller, Bryan W.; Morton, Jennifer P.; Bucher, Elmar; Taimen, Pekka; Virtakoivu, Reetta; Cao, Yihai; Sansom, Owen J.; Joensuu, Heikki; Ivaska, Johanna.

In: Journal of Clinical Investigation, Vol. 124, No. 3, 2014, p. 1069-1082.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis

AU - Arjonen, Antti

AU - Kaukonen, Riina

AU - Mattila, Elina

AU - Rouhi, Pegah

AU - Högnäs, Gunilla

AU - Sihto, Harri

AU - Miller, Bryan W.

AU - Morton, Jennifer P.

AU - Bucher, Elmar

AU - Taimen, Pekka

AU - Virtakoivu, Reetta

AU - Cao, Yihai

AU - Sansom, Owen J.

AU - Joensuu, Heikki

AU - Ivaska, Johanna

PY - 2014

Y1 - 2014

N2 - Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53.driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport ß1 integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53.driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.

AB - Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53.driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport ß1 integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53.driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.

U2 - 10.1172/JCI67280

DO - 10.1172/JCI67280

M3 - Article

VL - 124

SP - 1069

EP - 1082

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 3

ER -