학술논문
AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer
Document Type
article
Author
Agnete S.T. Engelsen; Katarzyna Wnuk-Lipinska; Sebastien Bougnaud; Fanny A. Pelissier Vatter; Crina Tiron; René Villadsen; Masaru Miyano; Maria L. Lotsberg; Noëlly Madeleine; Pouda Panahandeh; Sushil Dhakal; Tuan Zea Tan; Stacey D’mello Peters; Sturla Grøndal; Sura M. Aziz; Silje Nord; Lars Herfindal; Martha R. Stampfer; Therese Sørlie; Rolf A. Brekken; Oddbjørn Straume; Nils Halberg; Gro Gausdal; Jean Paul Thiery; Lars A. Akslen; Ole W. Petersen; Mark A. LaBarge; James B. Lorens
Source
iScience, Vol 23, Iss 11, Pp 101649- (2020)
Subject
Language
English
ISSN
2589-0042
Abstract
Summary: The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl+ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.