LEFTY1

A TGF-β Superfamily Member and Regulator of Cancer Stem Cell Renewal

Tumor initiation and progression rely on a subpopulation of self-renewing cancer stem cells. These cells promote new tumorigenic cells as well as play a major role in the growth and maintenance of cancer, leading to metastasis, therapy resistance, and tumor recurrence following treatment.

LEFTY1 is a member of the transforming growth factor beta (TGF-β) superfamily and an important developmental signaling protein during embryogenesis by its interaction with NODAL to direct the left-right axis. Recently, it has been implicated in the tumorigenesis of breast cancer. According to two major cancer genome databases (The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium), approximately 20% of human breast cancer samples show genetic amplification or modification of LEFTY1. Genetic suppression of LEFTY1 expression in breast cancer models showed significant tumor inhibition.

Tachyon is partnering with AbCellera Biologics Inc. to develop a therapeutic antibody, TACH204, to inhibit LEFTY1.

LEFTY1 Publications

Zabala M, Lobo NA, Antony J, Heitink LS, Gulati GS, Lam J, Parashurama N, Sanchez K, Adorno M, Sikandar SS, Kuo AH, Qian D, Kalisky T, Sim S, Li L, Dirbas FM, Somlo G, Newman A, Quake SR, Clarke MF. LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis. Cell Stem Cell. 2020 Aug 6;27(2):284-299.e8.

Kim DK, Cha Y, Ahn HJ, Kim G, Park KS. Lefty1 and lefty2 control the balance between self-renewal and pluripotent differentiation of mouse embryonic stem cells. Stem Cells Dev. 2014 Vol 23, 457–466.

Chen C, and Shen MM. Two modes by which Lefty proteins inhibit nodal signaling. Curr. Biol. 2004 Vol 14, 618–624.

Cheng SK, Olale F, Brivanlou AH, Schier AF. Lefty blocks a subset of TGFbeta signals by antagonizing EGF-CFC coreceptors. PLoS Biol. 2004 Feb;2(2):E30.

Ulloa L and Tabibzadeh S. Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth factor-beta receptor. J Biol Chem. 2001 Jun 15;276(24):21397-404.