Epithelial-Mesenchymal Transition Induces Podocalyxin to Promote Extravasation via Ezrin Signaling

Julia Fröse; Michelle B Chen; Katie E Hebron; Ferenc Reinhardt; Cynthia Hajal; Andries Zijlstra; Roger D Kamm; Robert A Weinberg

doi:10.1016/j.celrep.2018.06.092

Epithelial-Mesenchymal Transition Induces Podocalyxin to Promote Extravasation via Ezrin Signaling

Cell Rep. 2018 Jul 24;24(4):962-972. doi: 10.1016/j.celrep.2018.06.092.

Authors

Julia Fröse¹, Michelle B Chen², Katie E Hebron³, Ferenc Reinhardt⁴, Cynthia Hajal², Andries Zijlstra⁵, Roger D Kamm⁶, Robert A Weinberg⁷

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Faculty of Biosciences, University of Heidelberg, 69117 Heidelberg, Germany.
² Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Laboratory of Cellular and Molecular Biology, National Cancer Institute, NIH, Bethesda, MD, USA.
⁴ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
⁵ Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
⁶ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁷ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Ludwig/MIT Center for Molecular Oncology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: weinberg@wi.mit.edu.

Abstract

The epithelial-mesenchymal transition (EMT) endows carcinoma cells with traits needed to complete many of the steps leading to metastasis formation, but its contributions specifically to the late step of extravasation remain understudied. We find that breast cancer cells that have undergone an EMT extravasate more efficiently from blood vessels both in vitro and in vivo. Analysis of gene expression changes associated with the EMT program led to the identification of an EMT-induced cell-surface protein, podocalyxin (PODXL), as a key mediator of extravasation in mesenchymal breast and pancreatic carcinoma cells. PODXL promotes extravasation through direct interaction of its intracellular domain with the cytoskeletal linker protein ezrin. Ezrin proceeds to establish dorsal cortical polarity, enabling the transition of cancer cells from a non-polarized, rounded cell morphology to an invasive extravasation-competent shape. Hence, the EMT program can directly enhance the efficiency of extravasation and subsequent metastasis formation through a PODXL-ezrin signaling axis.

Keywords: EMT; PODXL; extravasation; ezrin; metastasis.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Breast Neoplasms / blood supply
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology*
Cell Line, Tumor
Cytoskeletal Proteins / metabolism*
Epithelial-Mesenchymal Transition
Female
Heterografts
Humans
Lung Neoplasms / metabolism
Lung Neoplasms / secondary
Male
Mice
Mice, Inbred NOD
Mice, SCID
Pancreatic Neoplasms / blood supply
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / pathology*
Sialoglycoproteins / genetics
Sialoglycoproteins / metabolism*
Signal Transduction

Substances

Cytoskeletal Proteins
Sialoglycoproteins
ezrin
podocalyxin

Abstract

Publication types

MeSH terms

Substances

Grants and funding