Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis
Antti Arjonen, … , Heikki Joensuu, Johanna Ivaska
Antti Arjonen, … , Heikki Joensuu, Johanna Ivaska
Published February 3, 2014
Citation Information: J Clin Invest. 2014;124(3):1069-1082. https://doi.org/10.1172/JCI67280.
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Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis

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 β1 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.

Authors

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

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Figure 4

Myo10 regulates invasion and metastasis in vivo.

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Myo10 regulates invasion and metastasis in vivo. (A and B) Labeled shCon...
(A and B) Labeled shControl and shMyo10 MDA-MB-231 cells were microinjected into zebrafish embryos, and dissemination (yellow arrowheads) was observed 4 days after implantation. Top panels show higher magnification regions of head-trunk and tail areas. Scale bars 500 μm (top panels); 100 μm (bottom panels). (C and D) Extravasation of shControl and shMyo10 MDA-MB-231 cells (C) or siMyo10 and siControl-transfected MDA-MB-468 and BT-474 breast cancer cells (D) into mouse lungs was studied in vivo. shMyo10/siMyo10 cells (green) and shControl/siControl cells (red) were coinjected (1:1) into the tail vein. After 48 hours, extravasated cells (arrowheads) were analyzed from lung sections visually (C) (12 sections/mouse) or by flow cytometry (D). Shown are representative lung sections stained with dapi. Scale bar: 300 μm (C and D). Area containing extravasated shControl cells is indicated with a dashed line. (E and F) Lung colonization of tail vein–injected unstained shControl and shMyo10 cells (4 weeks after injection). Shown are representative H&E stainings of lung tissue sections (E) (metastases indicated with asterisks) and FACS analysis of the human HLA or human vimentin–positive cells (%) of all the cells isolated from lungs (F). Scale bar: 100 μm. (G) Systemic spreading of shMyo10 or shControl cells injected orthotopically to mammary fat pads of nude mice was assessed after 6 weeks from frozen contralateral lymph nodes with vimentin staining, and primary tumors were stained for reference. Quantitation shows the number of mice with metastasis in the lymph nodes. Scale bar: 300 μm. Mean ± SEM and Mann Whitney test P values; n = 10 mice.