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

被引：128

作者：

Goyette, Marie-Anne ^{[1
,2
]}

Duhamel, Stephanie ^{[1
]}

Aubert, Leo ^{[3
]}

Pelletier, Ariane ^{[1
]}

Savage, Paul ^{[4
]}

Thibault, Marie-Pier ^{[1
]}

Johnson, Radia Marie ^{[4
]}

Carmeliet, Peter ^{[5
,6
]}

Basik, Mark ^{[7
]}

Gaboury, Louis ^{[8
]}

Muller, William J. ^{[4
]}

Park, Morag ^{[4
]}

Roux, Philippe P. ^{[3
,8
]}

Gratton, Jean-Philippe ^{[9
]}

Cote, Jean-Francois ^{[1
,2
,10
,11
]}

机构：

[1] Montreal Clin Res Inst IRCM, Montreal H2W 1R7, PQ H2W 1R7, Canada

[2] Univ Montreal, Mol Biol Programs, Montreal, PQ H3T 1J4, Canada

[3] Univ Montreal, IRIC, Montreal, PQ H3C 3J7, Canada

[4] McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ H3A 1A1, Canada

[5] VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, B-3000 Louvain, Belgium

[6] Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, B-3000 Leuven, Belgium

[7] McGill Univ, Sir Mortimer B Davis Jewish Gen Hosp, Lady Davis Inst Med Res, Segal Canc Ctr,Dept Oncol & Surg, Montreal, PQ H3T 1E2, Canada

[8] Univ Montreal, Dept Pathol & Cell Biol, Montreal, PQ H3C 3J7, Canada

[9] Univ Montreal, Dept Pharmacol & Physiol, Montreal, PQ H3C 3J7, Canada

[10] Univ Montreal, Dept Biochem & Mol Med, Montreal, PQ H3C 3J7, Canada

[11] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ H3A 0C7, Canada

来源：

CELL REPORTS | 2018年 / 23卷 / 05期

关键词：

TO-MESENCHYMAL TRANSITION; THERAPEUTIC TARGET; TUMOR PROGRESSION; OVARIAN-CANCER; CELL MOTILITY; TAM RECEPTORS; TGF-BETA; EXPRESSION; ACTIVATION; CARCINOMA;

D O I：

10.1016/j.celrep.2018.04.019

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 beta (TGF-beta)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.

引用

页码：1476 / 1490

页数：15

共 52 条

[41] Transforming growth factor β signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis [J].