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

Research output: Contribution to journalArticle

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

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
Pages (from-to)1384-1394
Number of pages11
JournalCancer Research
Volume72
Issue number6
DOIs
StatePublished - Mar 15 2012

PMID: 22282653

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Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. / Gao, Dingcheng; Joshi, Natasha; Choi, Hyejin; Ryu, Seongho; Hahn, Mary; Catena, Raul; Sadik, Helen; Argani, Pedram; Wagner, Patrick; Vahdat, Linda T.; Port, Jeffrey L.; Stiles, Brendon; Sukumar, Saraswati; Altorki, Nasser K.; Rafii, Shahin; Mittal, Vivek.

In: Cancer Research, Vol. 72, No. 6, 15.03.2012, p. 1384-1394.

Research output: Contribution to journalArticle

Harvard

Gao, D, Joshi, N, Choi, H, Ryu, S, Hahn, M, Catena, R, Sadik, H, Argani, P, Wagner, P, Vahdat, LT, Port, JL, Stiles, B, Sukumar, S, Altorki, NK, Rafii, S & Mittal, V 2012, 'Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition' Cancer Research, vol. 72, no. 6, pp. 1384-1394. https://doi.org/10.1158/0008-5472.CAN-11-2905

APA

Gao, D., Joshi, N., Choi, H., Ryu, S., Hahn, M., Catena, R., ... Mittal, V. (2012). Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Research, 72(6), 1384-1394. https://doi.org/10.1158/0008-5472.CAN-11-2905

Vancouver

Gao D, Joshi N, Choi H, Ryu S, Hahn M, Catena R et al. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Research. 2012 Mar 15;72(6):1384-1394. https://doi.org/10.1158/0008-5472.CAN-11-2905

Author

Gao, Dingcheng ; Joshi, Natasha ; Choi, Hyejin ; Ryu, Seongho ; Hahn, Mary ; Catena, Raul ; Sadik, Helen ; Argani, Pedram ; Wagner, Patrick ; Vahdat, Linda T. ; Port, Jeffrey L. ; Stiles, Brendon ; Sukumar, Saraswati ; Altorki, Nasser K. ; Rafii, Shahin ; Mittal, Vivek. / Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. In: Cancer Research. 2012 ; Vol. 72, No. 6. pp. 1384-1394.

BibTeX

@article{11ba637b5a494517924faf1dbb1be258,
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.",
author = "Dingcheng Gao and Natasha Joshi and Hyejin Choi and Seongho Ryu and Mary Hahn and Raul Catena and Helen Sadik and Pedram Argani and Patrick Wagner and Vahdat, {Linda T.} and Port, {Jeffrey L.} and Brendon Stiles and Saraswati Sukumar and Altorki, {Nasser K.} and Shahin Rafii and Vivek Mittal",
year = "2012",
month = "3",
day = "15",
doi = "10.1158/0008-5472.CAN-11-2905",
language = "English",
volume = "72",
pages = "1384--1394",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

RIS

TY - JOUR

T1 - Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition

AU - Gao, Dingcheng

AU - Joshi, Natasha

AU - Choi, Hyejin

AU - Ryu, Seongho

AU - Hahn, Mary

AU - Catena, Raul

AU - Sadik, Helen

AU - Argani, Pedram

AU - Wagner, Patrick

AU - Vahdat, Linda T.

AU - Port, Jeffrey L.

AU - Stiles, Brendon

AU - Sukumar, Saraswati

AU - Altorki, Nasser K.

AU - Rafii, Shahin

AU - Mittal, Vivek

PY - 2012/3/15

Y1 - 2012/3/15

N2 - 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.

AB - 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.

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U2 - 10.1158/0008-5472.CAN-11-2905

DO - 10.1158/0008-5472.CAN-11-2905

M3 - Article

VL - 72

SP - 1384

EP - 1394

JO - Cancer Research

T2 - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 6

ER -

ID: 3310066