Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition

Dingcheng Gao, Natasha Joshi, Hyejin Choi, Seongho Ryu, Mary Hahn, Raul Catena, Helen Sadik, Pedram Argani, Patrick Wagner, Linda T. Vahdat, Jeffrey L. Port, Brendon Stiles, Saraswati Sukumar, Nasser K. Altorki, Shahin Rafii, Vivek Mittal

Research output: Contribution to journalArticlepeer-review

226 Scopus citations


Tumors systemically initiate metastatic niches in distant target metastatic organs. These niches, composed of bone marrow-derived hematopoietic cells, provide permissive conditions for future metastases. However, the mechanisms by which these cells mediate outgrowth of metastatic tumor cells are not completely known. Using mouse models of spontaneous breast cancer, we show enhanced recruitment of bone marrow-derived CD11b +Gr1 + myeloid progenitor cells in the premetastatic lungs. Gene expression profiling revealed that the myeloid cells from metastatic lungs express versican, an extracellular matrix proteoglycan. Notably, versican in metastatic lungs was mainly contributed by the CD11b +Ly6C high monocytic fraction of the myeloid cells and not the tumor cells or other stromal cells. Versican knockdown in the bone marrow significantly impaired lung metastases in vivo, without impacting their recruitment to the lungs or altering the immune microenvironment. Versican stimulated mesenchymal to epithelial transition of metastatic tumor cells by attenuating phospho- Smad2 levels, which resulted in elevated cell proliferation and accelerated metastases. Analysis of clinical specimens showed elevated versican expression within the metastatic lung of patients with breast cancer. Together, our findings suggest that selectively targeting tumor-elicited myeloid cells or versican represents a potential therapeutic strategy for combating metastatic disease.

Original languageEnglish (US)
Pages (from-to)1384-1394
Number of pages11
JournalCancer research
Issue number6
StatePublished - Mar 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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