FAK competes for Src to promote migration against invasion in melanoma cells

Kolli-Bouhafs, K.; Sick, Emilie; Noulet, Fanny; Gies, Jean-Pierre; Mey, J. De; Rondé, Philippe

doi:10.1038/cddis.2014.329

Cited by 47 publications

(65 citation statements)

References 54 publications

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“…It has been hypothesized that focal adhesions sequester Src to areas at the periphery of the cell, reducing the pool of Src kinase available to phosphorylate invadopodia components (Chan et al, 2009). A similar phenotype was observed in melanoma, where suppression of focal adhesions led to decreased migration, but increased invadopodia (Kolli-Bouhafs et al, 2014). We show that ADAM12 knockdown significantly inhibited focal adhesion turnover.…”

Section: Discussionsupporting

confidence: 54%

ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions

Eckert

Santiago-Medina

Lwin

et al. 2017

Journal of Cell Science

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The Twist1 transcription factor promotes tumor invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) and invadopodiamediated extracellular matrix (ECM) degradation. The critical transcription targets of Twist1 for mediating these events remain to be uncovered. Here, we report that Twist1 strongly induces expression of a disintegrin and metalloproteinase 12 (ADAM12). We observed that the expression levels of Twist1 mRNA and ADAM12 mRNA are tightly correlated in human breast tumors. Knocking down ADAM12 blocked cell invasion in a 3D mammary organoid culture. Suppression of ADAM12 also inhibited Twist1-induced tumor invasion and metastasis in human breast tumor xenografts, without affecting primary tumor formation. Mechanistically, knockdown of ADAM12 in breast cancer cells significantly reduced invadopodia formation and matrix degradation, and simultaneously increased overall cell adhesion to the ECM. Live-imaging analysis showed that knockdown of ADAM12 significantly inhibited focal adhesion turnover. Mechanistically, both the disintegrin and metalloproteinase domains of ADAM12 are required for its function at invadopodia, whereas the metalloproteinase domain is dispensable for its function at focal adhesions. Taken together, these data suggest that ADAM12 plays a crucial role in tumor invasion and metastasis by regulating both invadopodia and focal adhesions.

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Section: Discussionsupporting

confidence: 54%

ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions

Eckert

Santiago-Medina

Lwin

et al. 2017

Journal of Cell Science

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“…Interestingly, the results obtained from the FAK-heterozygous mice were phenocopied using FAK kinase inhibitors (44). In addition, other studies have shown that FAK kinase activity negatively regulates invadopodia activity, thus inhibition of FAK can actually increase invasion (45,46). Given this complicated role of FAK, it remains possible that inhibition of FAK kinase activity may provide an advantage for cancer cell survival and invasion, resulting in enhanced metastasis, as observed here.…”

Section: Discussionmentioning

confidence: 99%

FAK Expression, Not Kinase Activity, Is a Key Mediator of Thyroid Tumorigenesis and Protumorigenic Processes

Kessler

Sharma

Zhou

et al. 2016

Molecular Cancer Research

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There are limited therapy options for advanced thyroid cancer, including papillary and anaplastic thyroid cancer (PTC and ATC). Focal Adhesion Kinase (FAK) regulates cell signaling by functioning as a scaffold and kinase. Previously we demonstrated that FAK is overexpressed and activated in thyroid cancer cells and human PTC clinical specimens. However, it remains unclear whether patients with advanced thyroid cancer will benefit from FAK inhibition. Therefore, the dual functions of FAK in mediating pro-tumorigenic processes and thyroid tumorigenesis were investigated. Evidence here shows that FAK expression predominantly regulates thyroid cancer cell growth, viability, and anchorage-independent growth. FAK inhibition, with PF-562,271 treatment, modestly reduced tumor volumes, while FAK depletion, through shRNA knockdown, significantly reduced tumor volumes in vivo. A role for FAK expression in tumor establishment was demonstrated in a model of PTC, where FAK knockdown tumors did not develop. FAK depletion also led to a significant decrease in overall metastatic burden. Interestingly, pretreatment with a FAK inhibitor resulted in a paradoxical increase in metastasis in a model of ATC, but decreased metastasis in a model of PTC. These data provide the first evidence that FAK expression is critical for the regulation of thyroid tumorigenic functions.

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“…In fact, cells that underwent EMT were shown to migrate less than pre-EMT cells, indicating that migration and invasion processes can be disjoined [44]. Kolli-Bouhafs and colleagues (2014) demonstrated that mutation on FAK kinase (Tyr397) induced decreased migration but increased invasive properties in B16F10 melanoma cells [47]. All these lead us to infer that increased invasion does not have to be accompanied by increased migration.…”

Section: Discussionmentioning

confidence: 99%

MiR-223-5p works as an oncomiR in vulvar carcinoma byTP63suppression

et al. 2016

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MiR-223-5p has been previously mentioned to be associated with tumor metastasis in HPV negative vulvar carcinomas, such as in several other tumor types. In the present study, we hypothesized that this microRNA would be important in vulvar cancer carcinogenesis and progression. To investigate this, we artificially mimicked miR-223-5p expression in a cell line derived from lymph node metastasis of vulvar carcinoma (SW962) and performed in vitro assays. As results, lower cell proliferation (p < 0.01) and migration (p < 0.001) were observed when miR-223-5p was overexpressed. In contrast, increased invasive potential of these cells was verified (p < 0.004). In silico search indicated that miR-223-5p targets TP63, member of the TP53 family of proteins, largely described with importance in vulvar cancer. We experimentally demonstrated that this microRNA is capable to decrease levels of p63 at both mRNA and protein levels (p < 0.001, and p < 0.0001; respectively). Also, a significant inverse correlation was observed between miR-223-5p and p63 expressions in tumors from patients (p = 0.0365). Furthermore, low p63 protein expression was correlated with deeper tumor invasion (p = 0.0491) and lower patient overall survival (p = 0.0494). Our study points out miR-223-5p overexpression as a putative pathological mechanism of tumor invasion and a promising therapeutic target and highlights the importance of both miR-223-5p and p63 as prognostic factors in vulvar cancer. Also, it is plausible that the evaluation of p63 expression in vulvar cancer at the biopsy level may bring important contribution on prognostic establishment and in elaborating better surgical approaches for vulvar cancer patients.

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FAK competes for Src to promote migration against invasion in melanoma cells

Cited by 47 publications

References 54 publications

ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions

ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions

FAK Expression, Not Kinase Activity, Is a Key Mediator of Thyroid Tumorigenesis and Protumorigenic Processes

MiR-223-5p works as an oncomiR in vulvar carcinoma byTP63suppression

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