Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization

Huang, Fang-Ke; Han, Shaoqin; Xing, Bowen; Huang, Jian; Liu, Bingqian; Bordeleau, François; Reinhart‐King, Cynthia A.; Zhang, J. Jillian; Huang, Xin‐Yun

doi:10.1038/ncomms8465

Cited by 118 publications

(163 citation statements)

References 60 publications

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“…Rat IgG1 PE-conjugated Antibody (IC005P), Mouse MARCO PE-conjugated Antibody (FAB2956P), Rat IgG2A PE-conjugated Antibody (IC006P), Mouse Fc gamma RI/CD64 PE-conjugated Antibody (FAB20741P), and Mouse MARCO Antibody (AF2956-SP) were purchased from R&D Systems. Rac1 inhibitor, NSC23766 (1177865-17-6, Cayman Chemical, Ann Arbor, MI, USA); N-WASP inhibitor, Wiskostatin (253449-04-6, Cayman Chemical); Arp2/3 complex inhibitor, CK666 (SML0006, Sigma-Aldrich, St. Louis, MO, USA); Fascin inhibitor (21), C 20 H 14 F 3 N 3 O 2 (L457698-1EA, Sigma-Aldrich). CytoPainter Phalloidin-iFluor 647 Reagent (ab176759) and Anti-Arp2 (phospho T237 + T238) antibody (ab119766) were purchased from abcam (Cambridge, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Aging-Impaired Filamentous Actin Polymerization Signaling Reduces Alveolar Macrophage Phagocytosis of Bacteria

Jiao

Fan

et al. 2017

The Journal of Immunology

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In elderly patients bacterial infection often causes severe complications and sepsis. Compared to younger patients, older patients are more susceptible to sepsis caused by respiratory infection. Macrophage (Mϕ) phagocytosis of bacteria plays a critical role in the clearance of pathogens and the initiation of immune responses. It has been suggested that Mϕ exhibit age related functional alterations, including reduced chemotaxis, phagocytosis, antibacterial defense, and ability to generate reactive oxygen species. However, the mechanisms behind these changes remain unclear. The current study aimed at determining changes in bacterial phagocytosis in aging alveolar Mϕ (AMϕ) and the underlying mechanisms. We show that bacteria initiate cytoskeleton remodeling in AMϕ through interaction with macrophage receptor with collagenous structure (MARCO), a bacterial scavenger receptor. This remodeling, in turn, promotes enhanced cell surface expression of MARCO and bacterial phagocytosis. We further demonstrate that Rac1-GTP mediates MARCO signaling and activates actin-related protein-2/3 (Arp2/3) complex, a filamentous actin (F-actin) nucleator, thereby inducing F-actin polymerization, filopodia formation, and increased cell surface expression of MARCO, all of which are essential for the execution of bacteria phagocytosis. However, AMϕ isolated from aging mice exhibit suppressed Rac1 mRNA and protein expression, which resulted in decreases in Rac1-GTP levels and Arp2/3 activation, and subsequent attenuation of F-actin polymerization, filopodia formation and cell surface expression of MARCO. As a result, bacterial phagocytosis in aging AMϕ is decreased. This study highlights a previously unidentified mechanism by which aging impairs Mϕ phagocytosis of bacteria. Targeting these pathways may improve outcomes of bacterial infection in elderly patients.

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Section: Methodsmentioning

confidence: 99%

Aging-Impaired Filamentous Actin Polymerization Signaling Reduces Alveolar Macrophage Phagocytosis of Bacteria

Jiao

Fan

et al. 2017

The Journal of Immunology

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“…Fascin-1 also promoted tumour progression in a mouse genetic model of pancreatic cancer 13. More recently, a small molecule that inhibits actin bundling by fascin-1 was reported to decrease lung metastasis of syngeneic fascin-1–positive breast tumours in mice 18. Therefore, fascin-1 has emerged as a new prospective therapeutic target 19,20…”

Section: Introductionmentioning

confidence: 99%

Analysis of Fascin-1 in Relation to Gleason Risk Classification and Nuclear ETS-Related Gene Status of Human Prostate Carcinomas: An Immunohistochemical Study of Clinically Annotated Tumours From the Wales Cancer Bank

et al. 2017

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Although prostate-specific antigen (PSA) testing can identify early-stage prostate cancers, additional biomarkers are needed for risk stratification. In one study, high levels of the actin-bundling protein, fascin-1, were correlated with lethal-phase, hormone-refractory prostate cancer. Analyses of independent samples are needed to establish the value of fascin-1 as a possible biomarker. We examined fascin-1 by immunohistochemistry in tumour specimens from the Wales Cancer Bank in comparison with nuclear-located ETS-related gene (ERG), an emerging marker for aggressive prostate cancer. Fascin-1 was elevated in focal areas of a minority of tumours, yet fascin-1-positivity did not differentiate tumours of low-, intermediate-, or high-risk Gleason scores and did not correlate with PSA status or biochemical relapse after surgery. Stromal fascin-1 correlated with high Gleason score. Nuclear ERG was upregulated in tumours but not in stroma. The complexities of fascin-1 status indicate that fascin-1 is unlikely to provide a suitable biomarker for prediction of aggressive prostate cancers.

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“…Fascin contains several actin binding sites (15), of which the N-terminal one can be inhibited by phosphorylation of a conserved serine (Ser-39) by means of PKC (16). Due to its up-regulation in many cancers and its association with mortality and metastasis, fascin has emerged as an important biomarker (17,18) and therapeutic target (19,20). However, fascin depletion does not abolish bundling in filopodia (12), and also normal epithelial cells devoid of fascin form filopodia (21) suggesting that other bundling proteins may be involved.…”

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confidence: 99%

Fascin Rigidity and L-plastin Flexibility Cooperate in Cancer Cell Invadopodia and Filopodia

Audenhove¹,

Denert²,

Boucherie³

et al. 2016

Journal of Biological Chemistry

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Invadopodia and filopodia are dynamic, actin-based protrusions contributing to cancer cell migration, invasion, and metastasis. The force of actin bundles is essential for their protrusive activity. The bundling protein fascin is known to play a role in both invadopodia and filopodia. As it is more and more acknowledged that functionally related proteins cooperate, it is unlikely that only fascin bundles actin in these protrusions. Another interesting candidate is L-plastin, normally expressed in hematopoietic cells, but considered a common marker of many cancer types. We identified L-plastin as a new component of invadopodia, where it contributes to degradation and invasiveness. By means of specific, high-affinity nanobodies inhibiting bundling of fascin or L-plastin, we further unraveled their cooperative mode of action. We show that the bundlers cannot compensate for each other due to strikingly different bundling characteristics: L-plastin bundles are much thinner and less tightly packed. Composite bundles adopt an intermediate phenotype, with fascin delivering the rigidity and strength for protrusive force and structural stability, whereas L-plastin accounts for the flexibility needed for elongation. Consistent with this, elevated L-plastin expression promotes elongation and reduces protrusion density in cells with relatively lower L-plastin than fascin levels.Filopodia are finger-like protrusions coordinating movement at the cell front by "sensing" extracellular stimuli (1). Invadopodia on the other hand are formed at the ventral cell side, enabling matrix degradation by localized proteolysis (2). As both actin-based protrusions contribute to migration and invasion, they are associated with cancer metastasis (3, 4), which has also been shown in vivo (5, 6).The architecture and dynamics of filopodia and invadopodia are controlled by a broad variety of actin-binding proteins (7,8). Moreover, these regulating proteins show highly similar spatial and temporal distributions in filopodia and invadopodia (9).

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Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization

Cited by 118 publications

References 60 publications

Aging-Impaired Filamentous Actin Polymerization Signaling Reduces Alveolar Macrophage Phagocytosis of Bacteria

Aging-Impaired Filamentous Actin Polymerization Signaling Reduces Alveolar Macrophage Phagocytosis of Bacteria

Analysis of Fascin-1 in Relation to Gleason Risk Classification and Nuclear ETS-Related Gene Status of Human Prostate Carcinomas: An Immunohistochemical Study of Clinically Annotated Tumours From the Wales Cancer Bank

Fascin Rigidity and L-plastin Flexibility Cooperate in Cancer Cell Invadopodia and Filopodia

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