SARS-CoV-2 infection induces EMT-like molecular changes, including ZEB1-mediated repression of the viral receptor ACE2, in lung cancer models

AbstractCOVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. We find that ACE2 expression is restricted to a select population of highly epithelial cells and is repressed by ZEB1, in concert with ZEB1’s established role in promoting epithelial to mesenchymal transition (EMT). Notably, infection of lung cancer cells with SARS-CoV-2 induces metabolic and transcriptional changes consistent with EMT, including upregulation of ZEB1 and AXL, thereby downregulating ACE2 post-infection. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state and lose ACE2 expression, along with its acute respiratory distress syndrome-protective effect, in a ZEB1-dependent manner. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect.

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Mechanical competition triggered by innate immune signaling drives the collective extrusion of bacterially-infected epithelial cells

10.1101/2020.01.22.915140 ◽

2020 ◽

Author(s):

Effie E. Bastounis ◽

Francisco Serrano Alcalde ◽

Prathima Radhakrishnan ◽

Patrik Engström ◽

María J. Gómez Benito ◽

...

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Bacterial Pathogens ◽

Innate Immune ◽

Host Cells ◽

Mammalian Host ◽

Rickettsia Parkeri ◽

Immune Signaling ◽

Mesenchymal Transition ◽

Innate Immune Signaling ◽

Infected Cells

SUMMARYMultiple distinct types of intracellular bacterial pathogens have been shown to alter the mechanics of their mammalian host cells to promote cell-to-cell spread. Conversely, host cells may respond by altering their own mechanical behavior to limit infection. We monitored epithelial cell monolayers sparsely infected with the intracellular bacterial pathogens Listeria monocytogenes or Rickettsia parkeri over the course of several days. Under conditions where these pathogens were able to trigger innate immune signaling through the NF-κB pathway and to use actin-based motility to spread non-lytically from cell to cell, domains of infected cells formed enormous three-dimensional mounds, where uninfected cells surrounding the infected cells became stiffer and actively moved toward the site of infection, collectively squeezing the softer and weaker infected cells up and ejecting them from the epithelial monolayer. Bacteria in mounds were less able to spread laterally in the monolayer, limiting the growth of the focus, while mounded cells eventually underwent cell death. Cells in infected monolayers exhibited behavioral and molecular signatures of the epithelial to mesenchymal transition (EMT), such that coordinated forceful action by uninfected bystander cells actively eliminated large domains of infected cells, consistent with the hypothesis that this collective cell response represents an innate immune response.

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Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner

Protein & Cell ◽

10.1007/s13238-020-00701-1 ◽

2020 ◽

Vol 11 (11) ◽

pp. 825-845

Author(s):

Weiwei Jiang ◽

Fangfang Cai ◽

Huangru Xu ◽

Yanyan Lu ◽

Jia Chen ◽

...

Keyword(s):

Lung Cancer ◽

Cell Migration ◽

Cell Motility ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Human Lung Cancer ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Promote Cell Migration ◽

Signaling Activation

Abstract This study was designed to evaluate ERK5 expression in lung cancer and malignant melanoma progression and to ascertain the involvement of ERK5 signaling in lung cancer and melanoma. We show that ERK5 expression is abundant in human lung cancer samples, and elevated ERK5 expression in lung cancer was linked to the acquisition of increased metastatic and invasive potential. Importantly, we observed a significant correlation between ERK5 activity and FAK expression and its phosphorylation at the Ser910 site. Mechanistically, ERK5 increased the expression of the transcription factor USF1, which could transcriptionally upregulate FAK expression, resulting in FAK signaling activation to promote cell migration. We also provided evidence that the phosphorylation of FAK at Ser910 was due to ERK5 but not ERK1/2, and we then suggested a role for Ser910 in the control of cell motility. In addition, ERK5 had targets in addition to FAK that regulate epithelial-to-mesenchymal transition and cell motility in cancer cells. Taken together, our findings uncover a cancer metastasis-promoting role for ERK5 and provide the rationale for targeting ERK5 as a potential therapeutic approach.

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Norcycloartocarpin targets Akt and suppresses Akt-dependent survival and epithelial-mesenchymal transition in lung cancer cells

PLoS ONE ◽

10.1371/journal.pone.0254929 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0254929

Author(s):

Nongyao Nonpanya ◽

Kittipong Sanookpan ◽

Keerati Joyjamras ◽

Duangdao Wichadakul ◽

Boonchoo Sritularak ◽

...

Keyword(s):

Lung Cancer ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Dermal Papilla ◽

Human Lung Cancer ◽

Dependent Manner ◽

Dermal Papilla Cells ◽

Mesenchymal Transition ◽

Protein Levels ◽

Dose Dependent

In searching for novel targeted therapeutic agents for lung cancer treatment, norcycloartocarpin from Artocarpus gomezianus was reported in this study to promisingly interacted with Akt and exerted the apoptosis induction and epithelial-to-mesenchymal transition suppression. Selective cytotoxic profile of norcycloartocarpin was evidenced with approximately 2-fold higher IC50 in normal dermal papilla cells (DPCs) compared with human lung cancer A549, H460, H23, and H292 cells. We found that norcycloartocarpin suppressed anchorage-independent growth, cell migration, invasion, filopodia formation, and decreased EMT in a dose-dependent manner at 24 h, which were correlated with reduced protein levels of N-cadherin, Vimentin, Slug, p-FAK, p-Akt, as well as Cdc42. In addition, norcycloartocarpin activated apoptosis caspase cascade associating with restoration of p53, down-regulated Bcl-2 and augmented Bax in A549 and H460 cells. Interestingly, norcycloartocarpin showed potential inhibitory role on protein kinase B (Akt) the up-stream dominant molecule controlling EMT and apoptosis. Computational molecular docking analysis further confirmed that norcycloartocarpin has the best binding affinity of -12.52 kcal/mol with Akt protein at its critical active site. As Akt has recently recognized as an attractive molecular target for therapeutic approaches, these findings support its use as a plant-derived anticancer agent in cancer therapy.

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Chronic IL-1β-Induced Inflammation Regulates Epithelial-to-Mesenchymal Transition Memory Phenotypes via Epigenetic Modification in Non-Small Cell Lung Cancer

SSRN Electronic Journal ◽

10.2139/ssrn.3417865 ◽

2019 ◽

Author(s):

Rui Li ◽

Stephanie L. Ong ◽

Linh M. Tran ◽

Zhe Jing ◽

Bin Liu ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Epithelial To Mesenchymal Transition ◽

Epigenetic Modification ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition

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Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

npj Precision Oncology ◽

10.1038/s41698-021-00203-1 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Marianne Oulhen ◽

Patrycja Pawlikowska ◽

Tala Tayoun ◽

Marianna Garonzi ◽

Genny Buson ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Copy Number ◽

Epithelial To Mesenchymal Transition ◽

Kinase Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition ◽

Anaplastic Lymphoma

AbstractGatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed highly altered CNA profiles and high levels of chromosomal instability (CIN). Half of CTCs displayed a ploidy >2n and 32% experienced whole-genome doubling. Hierarchical clustering showed significant intra-patient and wide inter-patient CTC diversity. Classification of 121 oncogenic drivers revealed the predominant activation of cell cycle and DNA repair pathways and of RTK/RAS and PI3K to a lower frequency. CTCs showed wide CNA heterogeneity and elevated CIN at resistance to ALK-TKIs. The emergence of epithelial ALK-negative CTCs may drive resistance through activation of bypass signaling pathways, while ALK-rearranged CTCs showed epithelial-to-mesenchymal transition characteristics potentially contributing to ALK-TKI resistance. Comprehensive analysis of CTCs could be of great help to clinicians for precision medicine and resistance to ALK-targeted therapies.

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Silent information regulator 1 suppresses epithelial-to-mesenchymal transition in lung cancer cells via its regulation of mitochondria status

Life Sciences ◽

10.1016/j.lfs.2021.119716 ◽

2021 ◽

pp. 119716

Author(s):

Jiaxin Zhang ◽

Jie Peng ◽

Deqin Kong ◽

Xiang Wang ◽

Zhao Wang ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Lung Cancer Cells ◽

Mesenchymal Transition ◽

Silent Information Regulator 1

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Ovalitenone Inhibits the Migration of Lung Cancer Cells via the Suppression of AKT/mTOR and Epithelial-to-Mesenchymal Transition

Molecules ◽

10.3390/molecules26030638 ◽

2021 ◽

Vol 26 (3) ◽

pp. 638

Author(s):

Kittipong Sanookpan ◽

Nongyao Nonpanya ◽

Boonchoo Sritularak ◽

Pithi Chanvorachote

Keyword(s):

Lung Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Colony Formation ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

A549 Cells ◽

Lung Cancer Cells ◽

Migration And Invasion ◽

Mesenchymal Transition

Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. Methods: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. Results: Ovalitenone was used at concentrations of 0–200 μM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. Conclusions: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.

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Pyrvinium pamoate inhibits cell proliferation through ROS-mediated AKT-dependent signaling pathway in colorectal cancer

Medical Oncology ◽

10.1007/s12032-021-01472-3 ◽

2021 ◽

Vol 38 (2) ◽

Author(s):

Wenqian Zheng ◽

Jinhui Hu ◽

Yiming Lv ◽

Bingjun Bai ◽

Lina Shan ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Epithelial To Mesenchymal Transition ◽

Flow Cytometric Analysis ◽

Inhibitory Effect ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Dependent Signaling Pathway ◽

Pyrvinium Pamoate

AbstractThe use of the anthelmintic drug pyrvinium pamoate (PP) in cancer therapy has been extensively investigated in the last decade. PP has been shown to have an inhibitory effect in colorectal cancer (CRC), but the underlying mechanism remains elusive. We aimed to investigate the antitumor activity and mechanisms of PP in CRC. In the present study, we used CCK-8 assays, colony formation assays, and western blotting to reveal that PP effectively suppressed CRC cell proliferation and the AKT-dependent signaling pathway in a concentration-dependent and time-dependent manner. Flow cytometric analysis and fluorescence microscopy demonstrated that PP increased intracellular reactive oxygen species (ROS) accumulation. We found that the inhibitory effect of PP on cell proliferation and AKT protein expression induced by PP could be partially reversed by N-acetyl-l-cysteine (NAC), an ROS scavenger. In addition, the results also demonstrated that PP inhibited cell migration by modulating epithelial-to-mesenchymal transition (EMT)-related proteins, including E-cadherin and vimentin. In conclusion, our data suggested that PP effectively inhibited cell proliferation through the ROS-mediated AKT-dependent signaling pathway in CRC, further providing evidence for the use of PP as an antitumor agent.

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