Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer

Cruz, Victoria H.; Arner, Emily N.; Du, Wenting; Bremauntz, Alberto; Brekken, Rolf A.

doi:10.1101/450049

Cited by 7 publications

(3 citation statements)

References 50 publications

(80 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TLR4 is known to cross signal with other receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR) (34), which is required for TLR4-dependent downstream signaling cascades that lead to proinflammatory cytokine production. Furthermore, there is considerable overlap between AXL signaling cascades and canonical TLR4 downstream effectors, including NF-κB, PI3k/Akt, and TBK1 (35)(36)(37), suggesting that the molecular mechanisms regulating crosstalk between AXL and TLR4 select for specific downstream effectors to determine functional outcomes. While a proximity ligation assay suggested close protein interactions between AXL and TLR4, AXL was dispensable for NF-κB signaling after TLR4 stimulation in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction

DeBerge¹,

Glinton²,

Subramanian³

et al. 2021

Journal of Clinical Investigation

View full text Add to dashboard Cite

Tyro3, AXL, and MerTK (TAM) receptors are activated in macrophages in response to tissue injury and as such have been proposed as therapeutic targets to promote inflammation resolution during sterile wound healing, including myocardial infarction. While the role of MerTK in cardioprotection is well-characterized, the unique role of the other structurally similar TAMs, and particularly AXL, in clinically-relevant models of myocardial ischemia-reperfused infarction (IRI) is comparatively unknown. Utilizing complementary approaches, validated by flow cytometric analysis of human and murine macrophage subsets and conditional genetic loss and gain of function, we uncover a unique maladaptive role for myeloid AXL during IRI in the heart. Cross signaling between AXL and TLR4 in cardiac macrophages directed a switch to glycolytic metabolism and secretion of proinflammatory IL-1β, leading to increased intramyocardial inflammation, adverse ventricular remodeling, and impaired contractile function. AXL functioned independently of cardioprotective MerTK to reduce the efficacy of cardiac repair, but like MerTK, was proteolytically cleaved. Administration of a selective small molecule AXL inhibitor alone improved cardiac healing, which was further enhanced in combination with blockade of MerTK cleavage. These data support further exploration of macrophage TAM receptors as therapeutic targets for myocardial infarction.

show abstract

Section: Discussionmentioning

confidence: 99%

Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction

DeBerge¹,

Glinton²,

Subramanian³

et al. 2021

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…The Tyro3-AXL-Mer (TAM) receptor tyrosine kinase AXL was shown to form a network that promotes migration and a partial epithelial-mesenchymal transition (EMT) in MCF-DCIS cells (26,31,32). Numerous studies have suggested the importance of AXL as a target in breast and other cancers (33–36) (37–41). AXL causes feed-forward transcriptional activation of Slug (SNAI2) through autocrine transforming growth factor (TGF) β signaling as well as more directly through SMAD3 (42,43).…”

Section: Resultsmentioning

confidence: 99%

WNK1 Enhances Migration and Invasion in Breast Cancer Models

Jaykumar

Jung

Parida

et al. 2021

Preprint

View full text Add to dashboard Cite

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.

show abstract

“…An initial study linking TBK1 to cancer found that TBK1 supports oncogenic Ras transformation with coupling innate immune signaling to tumor cell survival ( 10 ). Previous studies also demonstrated aberrant TBK1 expression and its pro-tumor effects in multiple cancers, including the promotion of migration and invasion in melanoma ( 11 ), AXL-induced epithelial–mesenchymal transition in pancreatic cancer ( 12 ), and tamoxifen resistance by increasing the transcriptional activity of estrogen receptor α in breast cancer ( 13 ). However, the underlying functions and mechanisms of TBK1 in HCC progression remain uncertain.…”

Section: Introductionmentioning

confidence: 92%

TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration

Jiang

Chen

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

BackgroundNumerous cancer types present the aberrant TANK-binding kinase 1 (TBK1) expression, which plays an important role in driving inflammation and innate immunity. However, the prognostic role of TBK1 and its relationship with immune cell infiltration in hepatocellular carcinoma (HCC) remain unclear.MethodsThe expression and prognostic value of TBK1 was analyzed by Tumor Immune Estimation Resource (TIMER), Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and further confirmed in the present cohort of patients with HCC. The association between TBK1 and HCC immune infiltrates, and its potential mechanism were investigated via analyses of the Tumor Immune Estimation Resource, tumor-immune system interactions database (TISIDB), CIBERSORT, STRING, and Metascape. The effect of TBK1 on immune infiltrates and the therapeutic value of targeting TBK1 were further investigated in a HCC mouse model by treatment with a TBK1 antagonist.ResultsThe level of TBK1 expression in HCC was higher than that measured in normal tissues, and associated with poorer overall survival (GEPIA: hazard ratio [HR]=1.80, P=0.038; Kaplan–Meier plotter: HR=1.87, P<0.001; CPTAC: HR=2.23, P=0.007; Our cohort: HR=2.92, P=0.002). In addition, high TBK1 expression was found in HCC with advanced TNM stage and identified as an independent poor prognostic factor for overall survival among patients with HCC. In terms of immune infiltration, tumor tissues from HCC patients with high TBK1 expression had a low proportion of CD8+ T cells, and TBK1 expression did not show prognostic value in HCC patients with enriched CD8+ T cells. Furthermore, TBK1 expression was positively correlated with the markers of T cell exhaustion and immunosuppressive cells in the HCC microenvironment. Mechanistically, the promotion of HCC immunosuppression by TBK1 was involved in the regulation of inflammatory cytokines. In vivo experiments revealed that treatment with a TBK1 antagonist delayed HCC growth by increasing the number of tumor-infiltrating CD8+ T cells.ConclusionsThe up-regulated expression of TBK1 may be useful in predicting poor prognosis of patients with HCC. In addition, TBK1, which promotes the HCC immunosuppressive microenvironment, may be a potential immunotherapeutic target for patients with HCC.

show abstract

Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer

Cited by 7 publications

References 50 publications

Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction

Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction

WNK1 Enhances Migration and Invasion in Breast Cancer Models

TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration

Contact Info

Product

Resources

About