A direct podocalyxin–dynamin-2 interaction regulates cytoskeletal dynamics to promote migration and metastasis in pancreatic cancer cells

Bin Sheng Wong, Daniel J. Shea, Panagiotis Mistriotis, Soontorn Tuntithavornwat, Robert A. Law, Jake M. Bieber, Lei Zheng, Konstantinos Konstantopoulos

Research output: Contribution to journalArticle

Abstract

The sialoglycoprotein podocalyxin is absent in normal pancreas but is overexpressed in pancreatic cancer and is associated with poor clinical outcome. Here, we investigate the role of podocalyxin in migration and metastasis of pancreatic adenocarcinomas using SW1990 and Pa03c as cell models. Although ezrin is regarded as a cytoplasmic binding partner of podocalyxin that regulates actin polymerization via Rac1 or RhoA, we did not detect podocalyxin–ezrin association in pancreatic cancer cells. Moreover, depletion of podocalyxin did not alter actin dynamics or modulate Rac1 and RhoA activities in pancreatic cancer cells. Using mass spectrometry, bioinformatics analysis, coimmunoprecipitation, and pull-down assays, we discovered a novel, direct binding interaction between the cytoplasmic tail of podocalyxin and the large GTPase dynamin-2 at its GTPase, middle, and pleckstrin homology domains. This podocalyxin–dynamin-2 interaction regulated microtubule growth rate, which in turn modulated focal adhesion dynamics and ultimately promoted efficient pancreatic cancer cell migration via microtubule- and Src-dependent pathways. Depletion of podocalyxin in a hemispleen mouse model of pancreatic cancer diminished liver metastasis without altering primary tumor size. Collectively, these findings reveal a novel mechanism by which podocalyxin facilitates pancreatic cancer cell migration and metastasis. Significance: These findings reveal that a novel interaction between podocalyxin and dynamin-2 promotes migration and metastasis of pancreatic cancer cells by regulating microtubule and focal adhesion dynamics.

Original languageEnglish (US)
Pages (from-to)2878-2891
Number of pages14
JournalCancer Research
Volume79
Issue number11
DOIs
StatePublished - Jun 1 2019

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Pancreatic Neoplasms
Neoplasm Metastasis
Dynamin II
Microtubules
Focal Adhesions
GTP Phosphohydrolases
Cell Movement
Actins
Sialoglycoproteins
podocalyxin
Liver Neoplasms
Computational Biology
Polymerization
Tail
Pancreas
Mass Spectrometry
Adenocarcinoma
Growth
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A direct podocalyxin–dynamin-2 interaction regulates cytoskeletal dynamics to promote migration and metastasis in pancreatic cancer cells. / Wong, Bin Sheng; Shea, Daniel J.; Mistriotis, Panagiotis; Tuntithavornwat, Soontorn; Law, Robert A.; Bieber, Jake M.; Zheng, Lei; Konstantopoulos, Konstantinos.

In: Cancer Research, Vol. 79, No. 11, 01.06.2019, p. 2878-2891.

Research output: Contribution to journalArticle

Wong, Bin Sheng ; Shea, Daniel J. ; Mistriotis, Panagiotis ; Tuntithavornwat, Soontorn ; Law, Robert A. ; Bieber, Jake M. ; Zheng, Lei ; Konstantopoulos, Konstantinos. / A direct podocalyxin–dynamin-2 interaction regulates cytoskeletal dynamics to promote migration and metastasis in pancreatic cancer cells. In: Cancer Research. 2019 ; Vol. 79, No. 11. pp. 2878-2891.
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