AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer

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. BrekkenOddbjørn Straume, Nils Halberg, Gro Gausdal, Jean Paul Thiery, Lars A. Akslen, Ole W. Petersen, Mark A. LaBarge, James B. Lorens

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number101649
JournaliScience
Volume23
Issue number11
DOIs
StatePublished - Nov 20 2020

Keywords

  • Cancer
  • Cell Biology
  • Stem Cells Research

ASJC Scopus subject areas

  • General

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