FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion

M. Gardberg (Corresponding Author), K. Kaipio, L. Lehtinen, P. Mikkonen, V.D. Heuser, K. Talvinen, Kristiina Iljin, C. Kampf, M. Uhlen, R. Grénman, M. Koivisto, O. Carpén

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Abstract

Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.
Original languageEnglish
Article number74923
JournalPLoS ONE
Volume8
Issue number9
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

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cell invasion
Epithelial-Mesenchymal Transition
cell movement
Cell Movement
Actins
Cells
Neoplasms
cells
Phosphatidylinositol 3-Kinases
actin
Plasticity
Tumors
mouth
Assays
Up-Regulation
Tissue
Squamous Cell Carcinoma
phosphatidylinositol 3-kinase
squamous cell carcinoma
microfilaments

Cite this

Gardberg, M., Kaipio, K., Lehtinen, L., Mikkonen, P., Heuser, V. D., Talvinen, K., ... Carpén, O. (2013). FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion. PLoS ONE, 8(9), [74923]. https://doi.org/10.1371/journal.pone.0074923
Gardberg, M. ; Kaipio, K. ; Lehtinen, L. ; Mikkonen, P. ; Heuser, V.D. ; Talvinen, K. ; Iljin, Kristiina ; Kampf, C. ; Uhlen, M. ; Grénman, R. ; Koivisto, M. ; Carpén, O. / FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion. In: PLoS ONE. 2013 ; Vol. 8, No. 9.
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abstract = "Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.",
author = "M. Gardberg and K. Kaipio and L. Lehtinen and P. Mikkonen and V.D. Heuser and K. Talvinen and Kristiina Iljin and C. Kampf and M. Uhlen and R. Gr{\'e}nman and M. Koivisto and O. Carp{\'e}n",
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Gardberg, M, Kaipio, K, Lehtinen, L, Mikkonen, P, Heuser, VD, Talvinen, K, Iljin, K, Kampf, C, Uhlen, M, Grénman, R, Koivisto, M & Carpén, O 2013, 'FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion', PLoS ONE, vol. 8, no. 9, 74923. https://doi.org/10.1371/journal.pone.0074923

FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion. / Gardberg, M. (Corresponding Author); Kaipio, K.; Lehtinen, L.; Mikkonen, P.; Heuser, V.D.; Talvinen, K.; Iljin, Kristiina; Kampf, C.; Uhlen, M.; Grénman, R.; Koivisto, M.; Carpén, O.

In: PLoS ONE, Vol. 8, No. 9, 74923, 2013.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion

AU - Gardberg, M.

AU - Kaipio, K.

AU - Lehtinen, L.

AU - Mikkonen, P.

AU - Heuser, V.D.

AU - Talvinen, K.

AU - Iljin, Kristiina

AU - Kampf, C.

AU - Uhlen, M.

AU - Grénman, R.

AU - Koivisto, M.

AU - Carpén, O.

PY - 2013

Y1 - 2013

N2 - Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.

AB - Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.

U2 - 10.1371/journal.pone.0074923

DO - 10.1371/journal.pone.0074923

M3 - Article

VL - 8

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 9

M1 - 74923

ER -