The Receptor Tyrosine Kinase AXL Is Required at Multiple Steps of the Metastatic Cascade during HER2-Positive Breast Cancer Progression

Marie-Anne Goyette; Stéphanie Duhamel; Léo Aubert; Ariane Pelletier; Paul Savage; Marie-Pier Thibault; Radia Marie Johnson; Peter Carmeliet; Mark Basik; Louis Gaboury; William J Muller; Morag Park; Philippe P Roux; Jean-Philippe Gratton; Jean-François Côté

doi:10.1016/j.celrep.2018.04.019

The Receptor Tyrosine Kinase AXL Is Required at Multiple Steps of the Metastatic Cascade during HER2-Positive Breast Cancer Progression

Cell Rep. 2018 May 1;23(5):1476-1490. doi: 10.1016/j.celrep.2018.04.019.

Authors

Affiliations

¹ Montreal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada; Molecular Biology Programs, Université de Montréal, Montréal, QC H3T 1J4, Canada.
² Montreal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada.
³ Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁴ Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A1, Canada.
⁵ Laboratory of Angiogenesis and Vascular Metabolism, VIB Vesalius Research Center, VIB, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, University of Leuven, Leuven 3000, Belgium.
⁶ Department of Oncology and Surgery, Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada.
⁷ Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁸ Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC H3C 3J7, Canada; Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁹ Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC H3C 3J7, Canada.
¹⁰ Montreal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada; Molecular Biology Programs, Université de Montréal, Montréal, QC H3T 1J4, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7, Canada. Electronic address: [email protected].

PMID: 29719259
DOI: 10.1016/j.celrep.2018.04.019

Abstract

AXL is activated by its ligand GAS6 and is expressed in triple-negative breast cancer cells. In the current study, we report AXL expression in HER2-positive (HER2⁺) breast cancers where it correlates with poor patient survival. Using murine models of HER2⁺ breast cancer, Axl, but not its ligand Gas6, was found to be essential for metastasis. We determined that AXL is required for intravasation, extravasation, and growth at the metastatic site. We found that AXL is expressed in HER2⁺ cancers displaying epithelial-to-mesenchymal transition (EMT) signatures where it contributes to sustain EMT. Interfering with AXL in a patient-derived xenograft (PDX) impaired transforming growth factor β (TGF-β)-induced cell invasion. Last, pharmacological inhibition of AXL specifically decreased the metastatic burden of mice developing HER2⁺ breast cancer. Our data identify AXL as a potential anti-metastatic co-therapeutic target for the treatment of HER2⁺ breast cancers.

Keywords: AXL; AXL inhibitor; EMT; HER2; PDX; breast cancer; metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Axl Receptor Tyrosine Kinase
Breast Neoplasms / genetics
Breast Neoplasms / mortality*
Breast Neoplasms / pathology
Epithelial-Mesenchymal Transition*
Female
Heterografts
Humans
Mice
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasm Transplantation
Proto-Oncogene Proteins / antagonists & inhibitors
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / metabolism*
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism*

Substances

Proto-Oncogene Proteins
ERBB2 protein, human
Receptor Protein-Tyrosine Kinases
Receptor, ErbB-2
Axl Receptor Tyrosine Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding