A complex containing LPP and α-Actinin mediates TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells

Ngan, Elaine; Northey, Jason J.; Brown, Claire M.; Ursini‐Siegel, Josie; Siegel, Peter M.

doi:10.1242/jcs.118315

Cited by 37 publications

(60 citation statements)

References 79 publications

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“…This sequential change in morphology is similar to that observed in AMT, which supports the idea that epithelial-like cancer cells are not affected by treatments that interfere with SIC metabolism because only mesenchymal-like cells can adopt an amoeboid morphology. This latter idea is further supported in studies that have used the well-established NMuMG and MDCK cell lines to induce EMT (Ngan et al, 2013;Yang et al, 2004); in both cell lines induction of EMT was only affected by a translation inhibitor upon mesenchymal induction. Although we failed to detect SICs in these cells, we recapitulate mechanisms that can usually be found during adhesion initiation in these structures.…”

Section: Discussionmentioning

confidence: 79%

“…proceed through EMT share mechanisms that are observed in SIC-positive cells. In order to determine whether the morphological state has an impact in SIC-dependent adhesion, we compared the adhesion kinetics of EMT-inducible NMuMG cells (Ngan et al, 2013;Northey et al, 2008). Transition of epithelial NMuMG cells towards mesenchymal-like cells was achieved by the transducing transcription factor Twist followed by sustained treatment with TGF-β (Miettinen et al, 1994;Yang et al, 2004).…”

Section: Adhesion-induced Translational Control Depends On Emtmentioning

confidence: 99%

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Localized translation regulates cell adhesion and transendothelial migration

Bergeman

Caillier

Houle

et al. 2016

Journal of Cell Science

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Epithelial-to-mesenchymal transition (EMT) is a process by which cancer cells gain the ability to leave the primary tumor site and invade surrounding tissues. These metastatic cancer cells can further increase their plasticity by adopting an amoeboid-like morphology, by undergoing mesenchymal-to-amoeboid transition (MAT). We found that adhering cells produce spreading initiation centers (SICs), transient structures that are localized above nascent adhesion complexes, and share common biological and morphological characteristics associated with amoeboid cells. Meanwhile, spreading cells seem to return to a mesenchymal-like morphology. Thus, our results indicate that SIC-induced adhesion recapitulates events that are associated with amoeboid-to-mesenchymal transition (AMT). We found that polyadenylated RNAs are enriched within SICs, blocking their translation decreased adhesion potential of metastatic cells that progressed through EMT. These results point to a so-farunknown checkpoint that regulates cell adhesion and allows metastatic cells to alter adhesion strength to modulate their dissemination.

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Section: Discussionmentioning

confidence: 79%

Section: Adhesion-induced Translational Control Depends On Emtmentioning

confidence: 99%

Localized translation regulates cell adhesion and transendothelial migration

Bergeman

Caillier

Houle

et al. 2016

Journal of Cell Science

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“…4C). Furthermore, we tested whether eIF4E knockdown would affect TGFb stimulated migration and invasion in activated ErbB2-transformed NMuMG cell lines, NT11L, and NT11R (29,28). Knockdown of eIF4E prevented TGFb induced cell migration and invasion in NT11L and NT11R, as determined in Transwell assays ( Fig.…”

Section: Knockdown or Functional Inhibition Of Eif4e Suppresses Tgfb-mentioning

confidence: 97%

“…The Transwell migration and invasion assays were performed as previously described (28,29). In brief, two independent NMuMG-ErbB2 explants (NT118L and NT118R) were transfected with control siRNA or eIF4E-specific siRNAs and incubated in the presence or absence of TGFb for 24 hours before plating into Boyden chambers.…”

Section: Migration and Invasion Transwell Assaymentioning

confidence: 99%

Genetic and Pharmacologic Inhibition of eIF4E Reduces Breast Cancer Cell Migration, Invasion, and Metastasis

et al. 2015

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The translation initiation factor eIF4E is an oncogene that is commonly overexpressed in primary breast cancers and metastases. In this article, we report that a pharmacologic inhibitor of eIF4E function, ribavirin, safely and potently suppresses breast tumor formation. Ribavirin administration blocked the growth of primary breast tumors in several murine models and reduced the development of lung metastases in an invasive model. Mechanistically, eIF4E silencing or blockade reduced the invasiveness and metastatic capability of breast cancer cells in a manner associated with decreased activity of matrix metalloproteinase (MMP)-3 and MMP-9. Furthermore, eIF4E silencing or ribavirin treatment suppressed features of epithelial-to-mesenchymal transition, a process crucial for metastasis. Our findings offer a preclinical rationale to explore broadening the clinical evaluation of ribavirin, currently being tested in patients with eIF4E-overexpressing leukemia, as a strategy to treat solid tumors such as metastatic breast cancer. Cancer Res; 75(6); 1102-12. Ó2015 AACR.

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“…It is also an inducer of EMT (32). Seven of the 23 trunk drivers are known human cancer genes, whereas five-Met, Lpp, Pbx1, lysine-specific demethylase 6A (Kdm6a), and Nf1-are reportedly involved in regulating EMT (32)(33)(34)(35)(36)(37). Another trunk driver, Rasa1, is a Ras GTPase-activating protein that suppresses oncogenic Ras signaling, another EMT inducer (5).…”

Section: Identification Of Ccgs Driving the Development Of Mesenchymalmentioning

confidence: 99%

Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

Kodama

Newberg

Kodama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMTTFs). Sequencing of transposon insertion sites from tumors identified 233 candidate cancer genes (CCGs) that were enriched for genes and cellular processes driving EMT. Subsequent trunk driver analysis identified 23 CCGs that are predicted to function early in tumorigenesis and whose mutation or alteration in patients with HCC is correlated with poor patient survival. Validation of the top trunk drivers identified in the screen, including MET (MET proto-oncogene, receptor tyrosine kinase), GRB2-associated binding protein 1 (GAB1), HECT, UBA, and WWE domain containing 1 (HUWE1), lysine-specific demethylase 6A (KDM6A), and protein-tyrosine phosphatase, nonreceptor-type 12 (PTPN12), showed that deregulation of these genes activates an EMT program in human HCC cells that enhances tumor cell migration. Finally, deregulation of these genes in human HCC was found to confer sorafenib resistance through apoptotic tolerance and reduced proliferation, consistent with recent studies showing that EMT contributes to the chemoresistance of tumor cells. Our unique cell-based transposon mutagenesis screen appears to be an excellent resource for discovering genes involved in EMT in human HCC and potentially for identifying new drug targets.H CC is the sixth most common cancer and the third-leading cause of cancer-related deaths worldwide (1). In the United States, the incidence of HCC is increasing, and overall 5-y survival is now <12%, despite recent progress in diagnostic and therapeutic modalities (2). This high mortality rate is related mainly to a high recurrence rate and associated intrahepatic or extrahepatic metastases (1). Patients with HCC who develop metastasis are no longer eligible for liver transplantation therapy and have very limited therapeutic options. Currently, sorafenib is the sole systemic antineoplastic agent for HCC described in the National Comprehensive Cancer Network (NCCN) guideline (3); however, its clinical benefit is limited (4), and alternative effective treatments are needed for these patients.Epithelial-mesenchymal transition (EMT) is a complex differentiation process whereby epithelial cells lose their identity and acquire mesenchymal characteristics (5). EMT is observed routinely in developmental processes, but is also believed to play an important role in the migration, invasion, and metastasis of various cancers (6-9). It also promotes the generation of cancer stem cells, thereby contributing to tumor recurrence and metastasis...

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A complex containing LPP and α-Actinin mediates TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells

Cited by 37 publications

References 79 publications

Localized translation regulates cell adhesion and transendothelial migration

Localized translation regulates cell adhesion and transendothelial migration

Genetic and Pharmacologic Inhibition of eIF4E Reduces Breast Cancer Cell Migration, Invasion, and Metastasis

Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

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