The BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic Sites

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Aug 21

PMID 22901808

Citations 238

Authors

Hua Gao

Goutam Chakraborty

Ai Ping Lee-Lim

Qianxing Mo

Markus Decker

Alin Vonica

Ronglai Shen

Edi Brogi

Ali H Brivanlou

Filippo G Giancotti

Affiliations

Soon will be listed here.

Abstract

The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-β ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung, but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific antimetastatic signals in order to undergo reactivation.

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References

Ellen T, Ke Q, Zhang P, Costa M . NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states. Carcinogenesis. 2007; 29(1):2-8. DOI: 10.1093/carcin/bgm200. View

Varga A, Wrana J . The disparate role of BMP in stem cell biology. Oncogene. 2005; 24(37):5713-21. DOI: 10.1038/sj.onc.1208919. View

Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C . The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011; 147(4):759-72. DOI: 10.1016/j.cell.2011.09.048. View

Gupta P, Chaffer C, Weinberg R . Cancer stem cells: mirage or reality?. Nat Med. 2009; 15(9):1010-2. DOI: 10.1038/nm0909-1010. View

Pylayeva Y, Gillen K, Gerald W, Beggs H, Reichardt L, Giancotti F . Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J Clin Invest. 2009; 119(2):252-66. PMC: 2631302. DOI: 10.1172/JCI37160. View

Valastyan S, Weinberg R . Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011; 147(2):275-92. PMC: 3261217. DOI: 10.1016/j.cell.2011.09.024. View

Clevers H . The cancer stem cell: premises, promises and challenges. Nat Med. 2011; 17(3):313-9. DOI: 10.1038/nm.2304. View

Pearce J, Penny G, Rossant J . A mouse cerberus/Dan-related gene family. Dev Biol. 1999; 209(1):98-110. DOI: 10.1006/dbio.1999.9240. View

Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M . VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell. 2011; 20(6):701-14. PMC: 3241854. DOI: 10.1016/j.ccr.2011.11.002. View

10.

Ben-Porath I, Thomson M, Carey V, Ge R, Bell G, Regev A . An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 2008; 40(5):499-507. PMC: 2912221. DOI: 10.1038/ng.127. View

11.

Tavazoie S, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos P . Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008; 451(7175):147-52. PMC: 2782491. DOI: 10.1038/nature06487. View

12.

van de Vijver M, He Y, Vant Veer L, Dai H, Hart A, Voskuil D . A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002; 347(25):1999-2009. DOI: 10.1056/NEJMoa021967. View

13.

Koh E, Chen T, Daley G . Novel retroviral vectors to facilitate expression screens in mammalian cells. Nucleic Acids Res. 2002; 30(24):e142. PMC: 140091. DOI: 10.1093/nar/gnf142. View

14.

Walsh D, Godson C, Brazil D, Martin F . Extracellular BMP-antagonist regulation in development and disease: tied up in knots. Trends Cell Biol. 2010; 20(5):244-56. DOI: 10.1016/j.tcb.2010.01.008. View

15.

Lo P, Kanojia D, Liu X, Singh U, Berger F, Wang Q . CD49f and CD61 identify Her2/neu-induced mammary tumor-initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGFβ signaling. Oncogene. 2011; 31(21):2614-26. PMC: 3260386. DOI: 10.1038/onc.2011.439. View

16.

Korpal M, Ell B, Buffa F, Ibrahim T, Blanco M, Celia-Terrassa T . Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med. 2011; 17(9):1101-8. PMC: 3169707. DOI: 10.1038/nm.2401. View

17.

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View

18.

Gupta G, Perk J, Acharyya S, de Candia P, Mittal V, Todorova-Manova K . ID genes mediate tumor reinitiation during breast cancer lung metastasis. Proc Natl Acad Sci U S A. 2007; 104(49):19506-11. PMC: 2148319. DOI: 10.1073/pnas.0709185104. View

19.

Minn A, Gupta G, Siegel P, Bos P, Shu W, Giri D . Genes that mediate breast cancer metastasis to lung. Nature. 2005; 436(7050):518-24. PMC: 1283098. DOI: 10.1038/nature03799. View

20.

Koh E, Chen T, Daley G . Genetic complementation of cytokine signaling identifies central role of kinases in hematopoietic cell proliferation. Oncogene. 2003; 23(6):1214-20. DOI: 10.1038/sj.onc.1207209. View