LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis

Maider Zabala; Neethan A Lobo; Jane Antony; Luuk S Heitink; Gunsagar S Gulati; Jessica Lam; Natesh Parashurama; Kassandra Sanchez; Maddalena Adorno; Shaheen S Sikandar; Angera H Kuo; Dalong Qian; Tomer Kalisky; Sopheak Sim; Linus Li; Frederick M Dirbas; George Somlo; Aaron Newman; Stephen R Quake; Michael F Clarke

doi:10.1016/j.stem.2020.06.017

LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis

Cell Stem Cell. 2020 Aug 6;27(2):284-299.e8. doi: 10.1016/j.stem.2020.06.017. Epub 2020 Jul 20.

Authors

Maider Zabala¹, Neethan A Lobo¹, Jane Antony¹, Luuk S Heitink¹, Gunsagar S Gulati¹, Jessica Lam¹, Natesh Parashurama², Kassandra Sanchez¹, Maddalena Adorno¹, Shaheen S Sikandar¹, Angera H Kuo¹, Dalong Qian¹, Tomer Kalisky³, Sopheak Sim¹, Linus Li¹, Frederick M Dirbas⁴, George Somlo⁵, Aaron Newman¹, Stephen R Quake⁶, Michael F Clarke⁷

Affiliations

¹ Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
² Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, NY, USA.
³ Department of Bioengineering, Stanford University, Stanford, CA, USA.
⁴ Department of Surgery, Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA, USA.
⁵ City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
⁶ Department of Bioengineering, Stanford University, Stanford, CA, USA; Chan Zuckerburg Biohub, San Francisco, CA, USA.
⁷ Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University, Stanford, CA, USA; Chan Zuckerburg Biohub, San Francisco, CA, USA. Electronic address: mfclarke@stanford.edu.

PMID: 32693087
DOI: 10.1016/j.stem.2020.06.017

Abstract

SMAD pathways govern epithelial proliferation, and transforming growth factor β (TGF-β and BMP signaling through SMAD members has distinct effects on mammary development and homeostasis. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. In contrast, BMP7, a NODAL antagonist with context-dependent functions, is produced by basal cells and restrains progenitor cell proliferation. In normal mouse epithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching. LEFTY1 binds BMPR2 to suppress BMP7-induced activation of SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cells in triple-negative breast cancer xenografts that rely on LEFTY1 for growth. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer.

Keywords: BMP7; BMPR2; Lefty1; SMAD2; SMAD5; breast; cancer; dual-SMAD; mammary; stem.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carcinogenesis
Cell Transformation, Neoplastic
Mice
Signal Transduction*
Transforming Growth Factor beta*

Substances

Transforming Growth Factor beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding