An Osteopontin/CD44 Axis in RhoGDI2-Mediated Metastasis Suppression

Mansoor Ahmed, Joseph L. Sottnik, Garrett M. Dancik, Divya Sahu, Donna E. Hansel, Dan Theodorescu, Martin A. Schwartz

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

RhoGDI2 specifically suppresses bladder cancer metastasis but not primary tumor growth, which involves tumor-associated macrophages. We report that macrophage-secreted osteopontin binds to CD44s on the tumor cells and promotes invasion and clonal growth. These effects are RhoGDI2-sensitive and require CD44s binding to the Rac GEF TIAM1. Osteopontin expression correlates with tumor aggressiveness and poor clinical outcome in patients. Inhibiting this pathway potently blocked lung and lymph node metastasis; however, primary tumors and established metastasis were less sensitive. Osteopontin-CD44s-TIAM1 promotes clonal growth in vitro but not at high cell density. These data identify osteopontin-CD44-TIAM1-Rac1 axis as a RhoGDI2-sensitive pathway and potential therapeutic target in bladder cancer metastasis. They also elucidate the mechanism behind RhoGDI2 specificity for metastasis over established tumors.

Original languageEnglish (US)
Pages (from-to)432-443
Number of pages12
JournalCancer Cell
Volume30
Issue number3
DOIs
StatePublished - Sep 12 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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