iScience (Nov 2020)
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. Brekken,
- Oddbjørn Straume,
- Nils Halberg,
- Gro Gausdal,
- Jean Paul Thiery,
- Lars A. Akslen,
- Ole W. Petersen,
- Mark A. LaBarge,
- James B. Lorens
Affiliations
- Agnete S.T. Engelsen
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway; Centre for Cancer Biomarkers, University of Bergen, 5021 Bergen, Norway; INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy Cancer Campus Grand Paris, 94800 Villejuif, France
- Katarzyna Wnuk-Lipinska
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway
- Sebastien Bougnaud
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway; Centre for Cancer Biomarkers, University of Bergen, 5021 Bergen, Norway
- Fanny A. Pelissier Vatter
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway; Centre for Cancer Biomarkers, University of Bergen, 5021 Bergen, Norway
- Crina Tiron
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway
- René Villadsen
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Copenhagen N 2200, Denmark
- Masaru Miyano
- Biolgical Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, CA 91910, USA
- Maria L. Lotsberg
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway; Centre for Cancer Biomarkers, University of Bergen, 5021 Bergen, Norway
- Noëlly Madeleine
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway
- Pouda Panahandeh
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway
- Sushil Dhakal
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway
- Tuan Zea Tan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- Stacey D’mello Peters
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway
- Sturla Grøndal
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway
- Sura M. Aziz
- Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Centre for Cancer Biomarkers, University of Bergen, 5021 Bergen, Norway; Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway
- Silje Nord
- Department of Cancer Research, Oslo University Hospital, 0310 Oslo, Norway
- Lars Herfindal
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway
- Martha R. Stampfer
- Biolgical Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
- Therese Sørlie
- Department of Cancer Research, Oslo University Hospital, 0310 Oslo, Norway
- Rolf A. Brekken
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Oddbjørn Straume
- Centre for Cancer Biomarkers, University of Bergen, 5021 Bergen, Norway; Department of Oncology and Medical Physics, Haukeland University Hospital, 5021 Bergen, Norway
- Nils Halberg
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway
- Gro Gausdal
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway
- Jean Paul Thiery
- Centre for Cancer Biomarkers, University of Bergen, 5021 Bergen, Norway; INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy Cancer Campus Grand Paris, 94800 Villejuif, France; Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, A-STAR, Singapore 138673, Singapore; Bioland Laboratory, Guangzhou Regenerative Medicine and Health, Bio-island, Guangzhou, 510320, China
- Lars A. Akslen
- Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Centre for Cancer Biomarkers, University of Bergen, 5021 Bergen, Norway; Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway
- Ole W. Petersen
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Copenhagen N 2200, Denmark; Novo Nordisk Foundation Center for Stem Cell Biology, University of Copenhagen, Copenhagen, Copenhagen N 2200, Denmark
- Mark A. LaBarge
- Centre for Cancer Biomarkers, University of Bergen, 5021 Bergen, Norway; Biolgical Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, CA 91910, USA; Corresponding author
- James B. Lorens
- Department of Biomedicine, University of Bergen, 5021 Bergen, Norway; Centre for Cancer Biomarkers, University of Bergen, 5021 Bergen, Norway; Corresponding author
- Journal volume & issue
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Vol. 23,
no. 11
p. 101649
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.
