Prometastatic NEDD9 Regulates Individual Cell Migration via Caveolin-1–Dependent Trafficking of Integrins

Kozyulina, Polina Y.; Loskutov, Yuriy V.; Kozyreva, Varvara K.; Rajulapati, Anuradha; Ice, Ryan J.; Jones, Brandon C.; Pugacheva, Elena N.

doi:10.1158/1541-7786.mcr-14-0353

Cited by 12 publications

(13 citation statements)

References 46 publications

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“…NEDD9 was depleted using previously characterized siRNAs (17, 32) (Fig.1A) in a SMARTpool, and the changes in individual cell morphology were monitored using live cell imaging microscopy when plated in 2D or suspended in 3D matrix (collagen I or Matrigel).…”

Section: Resultsmentioning

confidence: 99%

Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior

Jones

Kelley

Loskutov

et al. 2017

Molecular Cancer Research

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Commonly upregulated in human cancers, the scaffolding protein NEDD9/HEF1 is a known regulator of mesenchymal migration and cancer cell plasticity. However, the functional role of NEDD9 as a regulator of different migration/invasion modes in the context of breast cancer metastasis is currently unknown. Here, it is reported that NEDD9 is necessary for both mesenchymal and amoeboid individual cell migration/invasion in triple-negative breast cancer (TNBC). NEDD9 deficiency results in acquisition of the amoeboid morphology, but severely limits all types of cell motility. Mechanistically, NEDD9 promotes mesenchymal migration via VAV2-dependent Rac1 activation, and depletion of VAV2 impairs the ability of NEDD9 to activate Rac1. Additionally, NEDD9 supports a mesenchymal phenotype through stimulating polymerization of actin via promoting CTTN phosphorylation in an AURKA-dependent manner. Interestingly, an increase in RhoA activity in NEDD9-depleted cells does not facilitate a switch to functional amoeboid motility, indicating a role of NEDD9 in the regulation of downstream RhoA signaling effectors. Simultaneous depletion of NEDD9 or inhibition of AURKA in combination with inhibition of the amoeboid driver ROCK results in an additional decrease in cancer cell migration/invasion. Finally, we confirmed that a dual targeting strategy is a viable and efficient therapeutic approach to hinder the metastasis of breast cancer in xenograft models, showcasing the important need for further clinical evaluation of this regimen in order to impede the spread of disease and improve patient survival.

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Section: Resultsmentioning

confidence: 99%

Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior

Jones

Kelley

Loskutov

et al. 2017

Molecular Cancer Research

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“…NEDD9 is abundantly expressed in many breast cancer cell lines [32]. Overexpression of NEDD9 promotes migration and invasion of breast tumor cells [56, 59, 60] through mechanisms that include activating proteins of the focal adhesion complex (FAK and SRC) [56], mediating effects of TGFβ [61–63], increasing the expression and activity of matrix metalloproteases (MMPs) [59, 64], regulating trafficking and enzymatic recovery of MMPs and integrins [65, 66] increasing synthesis of tumor-associated glycocalyx [67], and down-regulating E-cadherin [60, 68] (Fig. 3).…”

Section: Altered Nedd9 Expression In Cancermentioning

confidence: 99%

“…3). In the absence of NEDD9, the trafficking of ligand-bound integrins from early to late endosomes was impaired, resulting in a significant decrease in degradation of ligand/integrin complexes and an increase in CAV1-mediated recycling of ligand-bound integrins from early endosomes back to the plasma membrane without ligand disengagement, thus leading to low adhesion and migration of breast cancer cells [65]. …”

Section: Altered Nedd9 Expression In Cancermentioning

confidence: 99%

“…NEDD9 and SRC negatively regulate expression of E-cadherin through upregulation of the SLUG and SNAIL transcription factors [60], and also by regulating SRC-dependent removal of E-cadherin from adherens junctions [68]. NEDD9 promotes trafficking of ligand-bound integrins from early to late endosomes and degradation of ligand/integrin complexes by inactivating caveolin (CAV1), which mediates recycling of ligand-bound integrins from early endosomes back to the plasma membrane [65]. NEDD9 regulates turnover of MMP14 and its enzymatic recovery through the late endosomes by suppressing Arf6 dependent trafficking of MMP14/TIMP2 complexes from early/sorting endosomes back to the surface.…”

Section: Figurementioning

confidence: 99%

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Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

Shagisultanova

Gaponova

Gabbasov

et al. 2015

Gene

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Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases. Downstream, NEDD9 regulation of partners including CRKL, WAVE, PI3K/AKT, ERK, E-cadherin, Aurora-A (AURKA), HDAC6, and others allow NEDD9 to influence functions as pleiotropic as migration, invasion, survival, ciliary resorption, and mitosis. In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins. These data strongly support the relevance of further development of NEDD9 as a biomarker for therapeutic resistance. Finally, we briefly discuss emerging evidence supporting involvement of NEDD9 in additional pathological conditions, including stroke and polycystic kidney disease.

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“…FACS was performed as previously described (32). The detailed protocol is provided in Supplementary Methods.…”

Section: Methodsmentioning

confidence: 99%

Combination of Eribulin and Aurora A Inhibitor MLN8237 Prevents Metastatic Colonization and Induces Cytotoxic Autophagy in Breast Cancer

Kozyreva

Kiseleva

Ice

et al. 2016

Molecular Cancer Therapeutics

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Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubule targeting drug eribulin on different stages of metastasis in triple negative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells providing foundation for the combination therapy. Mechanistically, AURKA inhibition induced cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. This preclinical data provides a new understanding of the mechanisms by which MLN8237 mediates its anti-metastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early stage solid tumors.

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Prometastatic NEDD9 Regulates Individual Cell Migration via Caveolin-1–Dependent Trafficking of Integrins

Cited by 12 publications

References 46 publications

Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior

Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

Combination of Eribulin and Aurora A Inhibitor MLN8237 Prevents Metastatic Colonization and Induces Cytotoxic Autophagy in Breast Cancer

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