Migrastatics—Anti-metastatic and Anti-invasion Drugs: Promises and Challenges

Gandalovičová, Aneta; Rösel, Daniel; Fernandes, Michael; Veselý, Pavel; Heneberg, Petr; Čermák, Vladimı́r; Petruželka, Luboš; Kumar, Sunil; Sanz-Moreno, Victoria; Brábek, Jan

doi:10.1016/j.trecan.2017.04.008

Cited by 273 publications

(231 citation statements)

References 139 publications

(158 reference statements)

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“…Although we have no evidence that inhibiting this pathway promotes cytotoxicity, the ability to block migration and invasion with so-called 'migrastatics' offers huge potential benefits in slowing disease progression in patients with solid cancers 51 .…”

Section: Discussionmentioning

confidence: 97%

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

O’Regan

Barone

Adib

et al. 2019

Preprint

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EML4-ALK is an oncogenic fusion present in ~5% lung adenocarcinomas. However, distinct EML4-ALK variants differ in the length of the EML4 microtubule-associated protein encoded within the fusion and are associated with a poorly understood variability in disease progression and therapeutic response. Here, we show that EML4-ALK variant 3, which is linked to accelerated metastatic spread and worse patient outcome, causes microtubule stabilization, formation of extended cytoplasmic protrusions, loss of cell polarity and increased cell migration. Strikingly, this is dependent upon the NEK9 kinase that interacts with the Nterminal region of EML4. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates cell migration in a manner that requires the downstream kinase NEK7 but not ALK activity. Moreover, elevated NEK9 is associated in patients with EML4-ALK V3 expression, as well as reduced progression-free and overall survival. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through recruitment of NEK9 and NEK7 to increase cell migration and that this represents a novel actionable pathway that drives disease progression in lung cancer.

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Section: Discussionmentioning

confidence: 97%

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

O’Regan

Barone

Adib

et al. 2019

Preprint

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“…1 However, past attempts to develop anti-metastasis drugs have not been efficacious in clinical trials. 2 Recent advancements in nanomedicine provide new opportunities to avoid some drawbacks of commonly used cancer drugs, as nanoparticles can cross biological barriers, enter target cells with high selectivity, and function inside cell in a controlled manner. 3–5 Nanoparticles have shown promise as anti-metastasis drug delivery vehicles targeting invasive or metastasized cancer cells, 6–8 and they could even function as anti-metastasis drugs without drug loading.…”

mentioning

confidence: 99%

Gold Nanorod Photothermal Therapy Alters Cell Junctions and Actin Network in Inhibiting Cancer Cell Collective Migration

et al. 2018

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Most cancer-related deaths come from metastasis. It was recently discovered that nanoparticles could inhibit cancer cell migration. While most researchers focus on single-cell migration, the effect of nanoparticle treatment on collective cell migration has not been explored. Collective migration occurs commonly in many types of cancer metastasis, where a group of cancer cells move together, which requires the contractility of the cytoskeleton filaments and the connection of neighboring cells by the cell junction proteins. Here, we demonstrate gold nanorods (AuNRs) and the introduction of near-infrared light could inhibit the cancer cell collective migration by altering the actin filaments and cell junctions with significantly triggered phosphorylation changes of essential proteins, using mass spectrometry-based phosphoproteomics. Further observation using super-resolution stochastic optical reconstruction microscopy (STORM) showed the actin cytoskeleton filament bundles were disturbed, which is difficult to differentiate under a normal fluorescence microscope. The decreased expression level of N-Cadherin junctions and morphological changes of tight junction protein zonula occludens 2 (ZO-2) were also observed. All these results indicate possible functions of the AuNRs treatments in regulating and remodeling the actin filaments and cell junction proteins, which contribute to decreasing cancer cell collective migration.

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“…Clinically, metastatic disease represents a major challenge and is responsible for more than 90% of deaths associated with solid tumours 265 . Conventional drugs for cancer treatment are largely cytostatic drugs aimed at targeting intrinsic cancer cell mechanisms such as cell cycle progression.…”

Section: Clinical Translation and Implicationsmentioning

confidence: 99%

“…Conventional drugs for cancer treatment are largely cytostatic drugs aimed at targeting intrinsic cancer cell mechanisms such as cell cycle progression. Although in many instances they are successful in reducing the size of primary tumours, they have been shown to have little effect on DTCs, potentially owing to the increased heterogeneity and significant mutational burden of DTCs, which facilitates efficient evasion of cell death 1, 265, 266 . Furthermore, evidence suggests that some chemotherapies may trigger metastasis through increasing intravasation 267 .…”

Section: Clinical Translation and Implicationsmentioning

confidence: 99%

“…Furthermore, evidence suggests that some chemotherapies may trigger metastasis through increasing intravasation 267 . Thus, much research has turned to finding drugs which interfere with cell motility, targeting phases such as cancer cell invasion and migration through the surrounding ECM 265 , intravasation, and extravasation.…”

Section: Clinical Translation and Implicationsmentioning

confidence: 99%

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Recent advances in understanding the complexities of metastasis

et al. 2018

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Tumour metastasis is a dynamic and systemic process. It is no longer seen as a tumour cell-autonomous program but as a multifaceted and complex series of events, which is influenced by the intrinsic cellular mutational burden of cancer cells and the numerous bidirectional interactions between malignant and non-malignant cells and fine-tuned by the various extrinsic cues of the extracellular matrix. In cancer biology, metastasis as a process is one of the most technically challenging aspects of cancer biology to study. As a result, new platforms and technologies are continually being developed to better understand this process. In this review, we discuss some of the recent advances in metastasis and how the information gleaned is re-shaping our understanding of metastatic dissemination.

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Migrastatics—Anti-metastatic and Anti-invasion Drugs: Promises and Challenges

Cited by 273 publications

References 139 publications

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

Gold Nanorod Photothermal Therapy Alters Cell Junctions and Actin Network in Inhibiting Cancer Cell Collective Migration

Recent advances in understanding the complexities of metastasis

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