The fibroblast Tiam1-osteopontin pathway modulates breast cancer invasion and metastasis

Kun Xu, Xuejun Tian, Sun Y. Oh, Mohammad Movassaghi, Stephen P. Naber, Charlotte Kuperwasser, Rachel J. Buchsbaum

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Background: The tumor microenvironment has complex effects in cancer pathophysiology that are not fully understood. Most cancer therapies are directed against malignant cells specifically, leaving pro-malignant signals from the microenvironment unaddressed. Defining specific mechanisms by which the tumor microenvironment contributes to breast cancer metastasis may lead to new therapeutic approaches against advanced breast cancer. Methods: We use a novel method for manipulating three-dimensional mixed cell co-cultures, along with studies in mouse xenograft models of human breast cancer and a histologic study of human breast cancer samples, to investigate how breast cancer-associated fibroblasts affect the malignant behaviors of breast cancer cells. Results: Altering fibroblast Tiam1 expression induces changes in invasion, migration, epithelial-mesenchymal transition, and cancer stem cell characteristics in associated breast cancer cells. These changes are both dependent on fibroblast secretion of osteopontin and also long-lasting even after cancer cell dissociation from the fibroblasts, indicating a novel Tiam1-osteopontin pathway in breast cancer-associated fibroblasts. Notably, inhibition of fibroblast osteopontin with low doses of a novel small molecule prevents lung metastasis in a mouse model of human breast cancer metastasis. Moreover, fibroblast expression patterns of Tiam1 and osteopontin in human breast cancers show converse changes correlating with invasion, supporting the hypothesis that this pathway in tumor-associated fibroblasts regulates breast cancer invasiveness in human disease and is thus clinically relevant. Conclusions: These findings suggest a new therapeutic paradigm for preventing breast cancer metastasis. Pro-malignant signals from the tumor microenvironment with long-lasting effects on associated cancer cells may perpetuate the metastatic potential of developing cancers. Inhibition of these microenvironment signals represents a new therapeutic strategy against cancer metastasis that enables targeting of stromal cells with less genetic plasticity than associated cancer cells and opens new avenues for investigation of novel therapeutic targets and agents.

Original languageEnglish (US)
Article number14
JournalBreast Cancer Research
Volume18
Issue number1
DOIs
StatePublished - Jan 28 2016

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Keywords

  • Agelastatin
  • Breast cancer
  • Cancer-associated fibroblast
  • Metastasis
  • Osteopontin
  • Tiam1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Xu, K., Tian, X., Oh, S. Y., Movassaghi, M., Naber, S. P., Kuperwasser, C., & Buchsbaum, R. J. (2016). The fibroblast Tiam1-osteopontin pathway modulates breast cancer invasion and metastasis. Breast Cancer Research, 18(1), [14]. https://doi.org/10.1186/s13058-016-0674-8