title: Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition.
abstract: 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.
authors.affiliation: Department of Cardiothoracic Surgery and Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, New York, New York, USA.
authors.forename: Dingcheng
authors.initials: D
authors.lastname: Gao
authors.forename: Natasha
authors.initials: N
authors.lastname: Joshi
authors.forename: Hyejin
authors.initials: H
authors.lastname: Choi
authors.forename: Seongho
authors.initials: S
authors.lastname: Ryu
authors.forename: Mary
authors.initials: M
authors.lastname: Hahn
authors.forename: Raul
authors.initials: R
authors.lastname: Catena
authors.forename: Helen
authors.initials: H
authors.lastname: Sadik
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Patrick
authors.initials: P
authors.lastname: Wagner
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vahdat
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Port
authors.forename: Brendon
authors.initials: B
authors.lastname: Stiles
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.forename: Nasser K
authors.initials: NK
authors.lastname: Altorki
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D039481:CD11b Antigen / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D051899:Smad2 Protein / Q000378:metabolism; D053675:Versicans / Q000096:biosynthesis / Q000235:genetics
chemical_list: D039481:CD11b Antigen; D051899:Smad2 Protein; D053675:Versicans