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

Engelsen, Agnete S.T.; Wnuk-Lipińska, Katarzyna; Bougnaud, Sébastien; Vatter, Fanny A. Pelissier; Tiron, Crina; Villadsen, René; Miyano, Masaru; Lotsberg, Maria Lie; Madeleine, Noëlly; Panahandeh, Pouda; Dhakal, Sushil; Tan, Tuan Zea; Peters, Stacey D’mello; Grøndal, Sturla Magnus; Aziz, Sura; Nord, Silje; Herfindal, Lars; Stampfer, Martha R.; Sørlie, Thérese; Brekken, Rolf A.; Straume, Oddbjørn; Halberg, Nils; Gausdal, Gro; Thiery, Jean Paul; Akslen, Lars A.; Petersen, Ole W.; LaBarge, Mark A.; Lorens, James B.

doi:10.1016/j.isci.2020.101649

Cited by 23 publications

(21 citation statements)

References 75 publications

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“…To investigate whether epithelial progenitors from HR epithelia exhibited differentiation biases, we performed clonal differentiation assays on receptor tyrosine kinase cKit (CD117)-expressing cells enriched by FACS. Mammary epithelial cells enriched for high expression of cKit are capable of multilineage differentiation, but there is a luminal bias 7,22 . After FACS enrichment, cKit + cells were attached to cover slips at clonal density, and daughter cells in the resulting colonies were assayed by immunofluorescence for the differentiation markers KRT14 and KRT19 after either 2 d or 7 d. Marker-based watershed segmentation identified single cells in images, followed by measurement of the mean fluorescent signal that corresponded to KRT14 or KRT19 expression.…”

Section: Hr Progenitors Have Differentiation Defects and A Basal Biasmentioning

confidence: 99%

Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations

et al. 2021

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During aging in the human mammary gland, luminal epithelial cells lose lineage fidelity by expressing markers normally expressed in myoepithelial cells. We hypothesize that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. In the present study, we show that histologically normal breast tissue from younger women who are susceptible to breast cancer, as a result of harboring a germline mutation in BRCA1, BRCA2 or PALB2 genes, exhibits hallmarks of accelerated aging. These include proportionately increased luminal epithelial cells that acquired myoepithelial markers, decreased proportions of myoepithelial cells and a basal differentiation bias or failure of differentiation of cKit+ progenitors. High-risk luminal and myoepithelial cells are transcriptionally enriched for genes of the opposite lineage, inflammatory- and cancer-related pathways. We have identified breast-aging hallmarks that reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk or the associated breast cancer subtype.

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Section: Hr Progenitors Have Differentiation Defects and A Basal Biasmentioning

confidence: 99%

Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations

et al. 2021

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“…It has been reported that while AKT1 and AKT2 are found in the cytoplasm and mitochondria, respectively, AKT3 is often found in the nucleus (29). We observed clear nuclear localization of AKT3 in MDA-MB-231 and MCF10A/slug cells (30) (Supplemental Figure 3A,B). Interestingly, AXL silencing in MCF10a/slug cells reduced AKT3 nuclear localization, suggesting that AXL mediates the nuclear localization of AKT3 (Supplemental Figure 3B).…”

Section: Resultsmentioning

confidence: 92%

AXL-TBK1 driven nuclear AKT3 promotes metastasis

Arner

Westcott²,

Hinz

et al. 2022

Preprint

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Epithelial-to-mesenchymal transition (EMT) contributes to tumor cell survival, immune evasion, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a higher likelihood of metastasis. AXL, a receptor tyrosine kinase, drives EMT and is implicated in tumor progression, metastasis, and therapy resistance in multiple cancer types including pancreatic cancer and breast cancer. TANK-binding kinase 1 (TBK1) is central to AXL-driven EMT yet, the mechanism of how TBK1 induces EMT remains unclear. Here, we report that AXL activation stimulates TBK1 binding and phosphorylation of AKT3. TBK1 activation of AKT3 drives binding and phosphorylation of slug/snail resulting in protection from proteasomal degradation and translocation of the complex into the nucleus. We show that nuclear translocation of AKT3 is required for AXL-driven EMT and metastasis. Congruently, nuclear AKT3 expression correlates with worse outcome in aggressive breast cancer. To advance AKT3 as a therapeutic target, an AKT3-isoform selective allosteric small molecule inhibitor, BGB214, was developed. BGB214 inhibits AKT3 nuclear translocation, EMT-TF stability, AKT3-mediated invasion of breast cancer cells and reduces tumor initiation in vivo. Our results suggest that AKT3 nuclear activity is an important feature of AXL-driven epithelial plasticity and that selective AKT3 inhibition represents a novel therapeutic avenue for treating aggressive cancer.

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“…This effect of WNK1 was independent of OSR1. AXL expression is associated with metastasis and poor prognosis in a variety of tumor types including breast cancer (40,47,53,54). BGB324 is a first-in-class AXL inhibitor, currently in phase II clinical trials, exhibiting promising therapeutic characteristics.…”

Section: Discussionmentioning

confidence: 99%

WNK1 Enhances Migration and Invasion in Breast Cancer Models

Jaykumar

Jung

Parida

et al. 2021

Preprint

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Metastasis is the major cause of mortality in breast cancer patients. Many signaling pathways have been linked to cancer invasiveness, but blockade of few protein components has succeeded in reducing metastasis. Thus, identification of proteins contributing to invasion that are manipulable by small molecules may be valuable in inhibiting spread of the disease. The protein kinase WNK1 (with no lysine (K) 1) has been suggested to induce migration of cells representing a range of cancer types. Analyses of mouse models and patient data have implicated WNK1 as one of a handful of genes uniquely linked to invasive breast cancer. Here we present evidence that inhibition of WNK1 slows breast cancer metastasis. We show that depletion or inhibition of WNK1 reduces migration of several breast cancer cell lines in wound healing assays and decreases invasion in collagen matrices. Furthermore, WNK1 depletion suppresses expression of AXL, a tyrosine kinase implicated in metastasis. Finally, we demonstrate that WNK inhibition in mice attenuates tumor progression and metastatic burden. These data showing reduced migration, invasion, and metastasis upon WNK1 depletion in multiple breast cancer models suggest that WNK1 contributes to the metastatic phenotype and that WNK1 inhibition may offer a therapeutic avenue for attenuating progression of invasive breast cancers.

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

Cited by 23 publications

References 75 publications

Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations

Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations

AXL-TBK1 driven nuclear AKT3 promotes metastasis

WNK1 Enhances Migration and Invasion in Breast Cancer Models

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