@article{a093368682ba422c97cafe87b4d75393,
title = "AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer",
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.",
keywords = "Cancer, Cell Biology, Stem Cells Research",
author = "Engelsen, {Agnete S.T.} and Katarzyna Wnuk-Lipinska and Sebastien Bougnaud and {Pelissier Vatter}, {Fanny A.} and Crina Tiron and Ren{\'e} Villadsen and Masaru Miyano and Lotsberg, {Maria L.} and No{\"e}lly Madeleine and Pouda Panahandeh and Sushil Dhakal and Tan, {Tuan Zea} and Peters, {Stacey D.mello} and Sturla Gr{\o}ndal and Aziz, {Sura M.} and Silje Nord and Lars Herfindal and Stampfer, {Martha R.} and Therese S{\o}rlie and Brekken, {Rolf A.} and Oddbj{\o}rn Straume and Nils Halberg and Gro Gausdal and Thiery, {Jean Paul} and Akslen, {Lars A.} and Petersen, {Ole W.} and LaBarge, {Mark A.} and Lorens, {James B.}",
note = "Funding Information: This work was partly supported by the Research Council of Norway through its Centers of Excellence funding scheme, project number 223250 (CCBIO affiliates). JBL was supported by grants from the Norwegian Research Council (grant number 204868 ), and Norwegian Cancer Society (grant number 190330 ). ML from the National Institutes of Health ( R01AG040081 and R00AG033176 ), and United States Congressionally Directed Medical Research Program's Era of Hope Scholar Award ( BC141351 ). ASTE was supported by an FRIPRO Mobility Grant Fellowship from the Research Council of Norway co-funded by the EU's seventh Framework Program's Marie Sk{\l}odowska Curie Actions (MSCA COFUND, grant agreement number 608695 ). Support by Legat for Forskning av Kreftsykdommer fund at UIB, and Familien Blix fund to ASTE for the conduct of this study is greatly appreciated. Graphical abstract was created with BioRender.com . Funding Information: The authors are grateful to Dr. Janice Nigro for invaluable advice, language and manuscript editing. Thanks to Sissel Vik Berge, Endre Stigen, Ingrid Gavlen, Bendik Nordanger, and Jason Toombs for excellent technical support, Brith Bergum and Marianne Enger at the Flow Cytometry Core Facility at UiB, and Endy Spriet and Hege Avsnes Dale at the Molecular Imaging Center, UiB. The authors thank Dr. Kjell Petersen, Computational Biology Unit and, Norwegian Bioinformatics Platform, UiB, for microarray analysis support. The authors are grateful to the staff at the animal facility at the University of Bergen for their skillful maintenance and care of the research animals. And finally, the authors express their thanks to the women that consented to the use of their reduction mammoplasty tissue and biopsy tissue for this research. This work was partly supported by the Research Council of Norway through its Centers of Excellence funding scheme, project number 223250 (CCBIO affiliates). JBL was supported by grants from the Norwegian Research Council (grant number 204868), and Norwegian Cancer Society (grant number 190330). ML from the National Institutes of Health (R01AG040081 and R00AG033176), and United States Congressionally Directed Medical Research Program's Era of Hope Scholar Award (BC141351). ASTE was supported by an FRIPRO Mobility Grant Fellowship from the Research Council of Norway co-funded by the EU's seventh Framework Program's Marie Sk{\l}odowska Curie Actions (MSCA COFUND, grant agreement number 608695). Support by Legat for Forskning av Kreftsykdommer fund at UIB, and Familien Blix fund to ASTE for the conduct of this study is greatly appreciated. Graphical abstract was created with BioRender.com. Conception and design: M.A.L, J.B.L. Development of methodology: A.S.T.E, K.W-L, S.B, F.A.P.V, R.V, C.T, M.M, S.G. M.R.S, M.A.L, J.B.L. Acquisition of data: (provided animals, acquired and managed patients, provided facilities, etc.): A.S.T.E, K.W-L, S.B, F.A.P.V, C.T, M.M, O.S. Analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis): A.S.T.E, K. W-L, S.B, F.A.P.V, M.L.L, R.V, S.D, S.D'M.P, C.T, M. M, P. P, N.M. S.M.A, S.N, M.R.S, R.V, T. S, R.A.B, O.S, N.H, T.Z.T, J.P.T, L.A.A, O.P, M.A.L, J.B.L. Writing, review, and/or revision of the manuscript: A.S.T.E, K.W-L, M.L.L, J.P.T, O.P, R.V, M.A.L, J.B.L. Administrative, technical, or material support (i.e. reporting or organizing data, constructing databases): R.V, S.N, L.H, G.G, M.R.S, T.S, R.A.B, O.S, N.H, L.A.A, O.P, M.A.L, J.B.L. Study supervision: M.A.L, J.B.L. J.B.L. is founder and shareholder of BerGenBio ASA. K.W.L. G.G. and J.B.L. are former or current employees of BerGenBio ASA. J.P.T. is scientific founder and CSO of Biocheetah Pte Ltd Singapore and consultant/shareholder Biosyngen Pte Lte Limited and ACTgenomics Taipei Taiwan. S.C. and R.A.B. signed Sponsored Research Agreements with BerGenBio ASA related to a separate research project. The remaining authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = nov,
day = "20",
doi = "10.1016/j.isci.2020.101649",
language = "English (US)",
volume = "23",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "11",
}