scholarly journals EphB6 regulates TFEB-lysosomal pathway and survival of disseminated quiescent breast cancer cells

2020 ◽  
Author(s):  
Manuela Zangrossi ◽  
Probir Chakravarty ◽  
Patrizia Romani ◽  
Colin D.H. Ratcliffe ◽  
Steven Hooper ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Cancer Cells ◽  
Lung Epithelial Cells ◽  
Late Relapse ◽  
Alveolar Type ◽  
Type I ◽  
Extrinsic Factors ◽  
Lung Epithelial

AbstractLate relapse of disseminated cancer cells is a common feature of some types of tumors. Several intrinsic and extrinsic factors have been shown to affect reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining survival of DDCCs in a foreign environment are still poorly understood. We have recently shown that crosstalk with lung epithelial cells promotes persistence of DDCCs from estrogen receptor positive (ER+) breast tumors. Here we show that TFEB-lysosomal axis is activated in DDCCs and that it is modulated by the pro-survival ephrin receptor EphB6. TFEB lysosomal direct targets are enriched in DDCCs in vivo and correlate with relapse in ER+ breast cancer patients. Direct contact of DDCCs with alveolar type I-like lung epithelial cells drives lysosomal accumulation and EphB6 induction. EphB6 contributes to TFEB transcriptional activity and lysosome formation in DDCCs in vitro and in vivo, and supports survival of DDCCs in coculture and in vivo. Furthermore, signaling from EphB6 promotes the proliferative response of surrounding lung parenchymal cells in vivo.

scholarly journals EphB6 Regulates TFEB-Lysosomal Pathway and Survival of Disseminated Indolent Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1079
Author(s):  
Manuela Zangrossi ◽  
Patrizia Romani ◽  
Probir Chakravarty ◽  
Colin D.H. Ratcliffe ◽  
Steven Hooper ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Cancer Cells ◽  
Lung Epithelial Cells ◽  
Late Relapse ◽  
Alveolar Type ◽  
Type I ◽  
Extrinsic Factors ◽  
Lung Epithelial

Late relapse of disseminated cancer cells is a common feature of breast and prostate tumors. Several intrinsic and extrinsic factors have been shown to affect quiescence and reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining the survival of DDCCs in a foreign environment are still poorly understood. We have recently shown that crosstalk with lung epithelial cells promotes survival of DDCCs of estrogen receptor-positive (ER+) breast tumors. By using a lung organotypic system and in vivo dissemination assays, here we show that the TFEB-lysosomal axis is activated in DDCCs and that it is modulated by the pro-survival ephrin receptor EphB6. TFEB lysosomal direct targets are enriched in DDCCs in vivo and correlate with relapse in ER+ breast cancer patients. Direct coculture of DDCCs with alveolar type I-like lung epithelial cells and dissemination in the lung drive lysosomal accumulation and EphB6 induction. EphB6 contributes to survival, TFEB transcriptional activity, and lysosome formation in DDCCs in vitro and in vivo. Furthermore, signaling from EphB6 promotes the proliferation of surrounding lung parenchymal cells in vivo. Our data provide evidence that EphB6 is a key factor in the crosstalk between disseminated dormant cancer cells and the lung parenchyma and that the TFEB-lysosomal pathway plays an important role in the persistence of DDCCs.

scholarly journals A Lung Organotypic Coculture Reveals a Role for TFEB-Lysosomal Axis in the Survival of Disseminated Dormant Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1007
Author(s):  
Manuela Zangrossi ◽  
Probir Chakravarty ◽  
Patrizia Romani ◽  
Sirio Dupont ◽  
Steven Hooper ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Disease Free Survival ◽  
Lung Epithelial Cells ◽  
Alveolar Type ◽  
Type I ◽  
Sequencing Analysis ◽  
Metastatic Relapse

(1) Background: metastatic relapse following a prolonged period of disease-free survival is a common cause of mortality for many cancer patients. Disseminated dormant cancer cells (DDCCs) lie below the radar before waking up years, or even decades, after the removal of the primary tumor. This implies that they are able to survive in a latent state in a foreign environment for an extended period of time supported by intrinsic and extrinsic factors still to be elucidated. (2) Methods: we employed a coculture of DDCCs with lung epithelial cells together with RNA sequencing analysis to understand the overlap in gene transcription between in vivo and cocultured DDCCs. (3) Results: we found a significant overlap between the processes activated in DDCCs from lungs and in the coculture, as well as in alveolar type I cells in vivo and in coculture. We identified the transcription factor EB (TFEB)-lysosomal axis as a relevant process activated in DDCCs upon dissemination to the lung and confirmed the results in our lung coculture. Interestingly, breast cancer patients with a higher expression of TFEB targets show increased likelihood of developing relapses. (4) Conclusions: we propose that lysosomal accumulation following TFEB activation is an important feature of breast cancer DDCCs that might be exploited for future therapeutic interventions.

scholarly journals Lung Epithelial Cells Induce Both Phenotype Alteration and Senescence in Breast Cancer Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (1) ◽  
pp. e0118060 ◽  
Author(s):  
Masashi Furukawa ◽  
Sarah Wheeler ◽  
Amanda M. Clark ◽  
Alan Wells
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Lung Epithelial Cells ◽  
Lung Epithelial

scholarly journals CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation

2019 ◽  
Vol 2 (6) ◽  
pp. e201900460
Author(s):  
Evangelia Chavdoula ◽  
David M Habiel ◽  
Eugenia Roupakia ◽  
Georgios S Markopoulos ◽  
Eleni Vasilaki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Transcriptome Profiling ◽  
Lung Epithelial Cells ◽  
Tumor Promoter ◽  
Alveolar Type ◽  
Hypoxic Conditions ◽  
Lung Epithelial

Through the progressive accumulation of genetic and epigenetic alterations in cellular physiology, non–small-cell lung cancer (NSCLC) evolves in distinct steps involving mutually exclusive oncogenic mutations in K-Ras or EGFR along with inactivating mutations in the p53 tumor suppressor. Herein, we show two independent in vivo lung cancer models in which CHUK/IKK-α acts as a major NSCLC tumor suppressor. In a novel transgenic mouse strain, wherein IKKα ablation is induced by tamoxifen (Tmx) solely in alveolar type II (AT-II) lung epithelial cells, IKKα loss increases the number and size of lung adenomas in response to the chemical carcinogen urethane, whereas IKK-β instead acts as a tumor promoter in this same context. IKKα knockdown in three independent human NSCLC lines (independent of K-Ras or p53 status) enhances their growth as tumor xenografts in immune-compromised mice. Bioinformatics analysis of whole transcriptome profiling followed by quantitative protein and targeted gene expression validation experiments reveals that IKKα loss can result in the up-regulation of activated HIF-1-α protein to enhance NSCLC tumor growth under hypoxic conditions in vivo.

The Downregulation of Long Noncoding RNA Metastasis Associated with Colon Cancer 1 (lncRNA MACC1-AS1) Inhibits the Migration and Invasion of Non-Small Cell Lung Cancer Cells

2021 ◽  
Vol 11 (3) ◽  
pp. 453-457
Author(s):  
Caidi Zhang ◽  
Xinzhong Zou
Keyword(s):  
Lung Cancer ◽  
Epithelial Cells ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Small Cell ◽  
Lung Epithelial Cells ◽  
Normal Lung ◽  
Small Cell Lung ◽  
Lung Epithelial

To explore the effects of lncRNA MACC1-AS1 on the invasion and migration of non-small cell lung cancer (NSCLC), PCR was used to detect and compare lncRNA MACC1-AS1 expression in NSCLC cells to normal lung epithelial cells and assess the knockdown effect of lncRNA MACC1-AS1 in A549 and H1299 cell lines. The Transwell system was employed to compare the invasiveness of the lncRNA MACC1-AS1 knockdown cells to the control cells. The migratory ability of the lncRNA MACC1-AS1 knockdown cells was compared to the control cells via in vitro scratch assay. Western blot was used to detect the E-cadherin/N-cadherin expression. Balb/c mouse model was used to verify the metastasis ability in vivo between the control and lncRNA MACC1-AS1 knockdown groups. The level of lncRNA MACC1-AS1 was markedly higher in lung cancer cells than normal lung epithelial cells. The knockdown of lncRNA MACC1-AS1 reduced the invasiveness and migratory capacity of A549 and H1299 cells. Downregulating lncRNA MACC1-AS1 upregulated E-cadherin but down-regulated N-cadherin in A549 and H1299 cells. Besides, the silencing of lncRNA MACC1-AS1 reduced the A549 cells’ ability to metastasize in vivo. LncRNA MACC1-AS1 can enhance the invasiveness and migratory capability of NSCLC.

scholarly journals Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

2020 ◽  
Author(s):  
Guangchun Han ◽  
Ansam Sinjab ◽  
Warapen Treekitkarnmongkol ◽  
Patrick Brennan ◽  
Kieko Hara ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Single Cell ◽  
Expression Patterns ◽  
Severe Pneumonia ◽  
Lung Epithelial Cells ◽  
Chronic Obstructive ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii ◽  
Lung Epithelial

ABSTRACTThe novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understand ACE2 abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressing ACE2 was low (1.7% overall), alveolar type II (AT2, 2.2% ACE2+) cells exhibited highest levels of ACE2 expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed with ACE2 that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD; HHIP), pneumonia and infection (FGG and C4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably, DMBT1 was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated with ACE2. We describe a population of ACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g. DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.

scholarly journals In Vivo and In Vitro Analysis of Factor Binding Sites in Jaagsiekte Sheep Retrovirus Long Terminal Repeat Enhancer Sequences: Roles of HNF-3, NF-I, and C/EBP for Activity in Lung Epithelial Cells

2006 ◽  
Vol 80 (1) ◽  
pp. 332-341 ◽  
Author(s):  
Kathleen McGee-Estrada ◽  
Hung Fan
Keyword(s):  
Epithelial Cells ◽  
Long Terminal Repeat ◽  
Binding Site ◽  
Terminal Repeat ◽  
Lung Epithelial Cells ◽  
Type Ii ◽  
Jaagsiekte Sheep Retrovirus ◽  
Efficient System ◽  
Lung Epithelial

ABSTRACT Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma, a contagious lung cancer of sheep that arises from type II pneumocytes and Clara cells of the lung epithelium. Studies of the tropism of this virus have been hindered by the lack of an efficient system for viral replication in tissue culture. To map regulatory regions important for transcriptional activation, an in vivo footprinting method that couples dimethyl sulfate treatment and ligation-mediated PCR was performed in murine type II pneumocyte-derived MLE-15 cells infected with a chimeric Moloney murine leukemia virus driven by the JSRV enhancers (ΔMo+JS Mo-MuLV). In vivo footprints were found in the JSRV enhancers in two regions previously shown to be important for JSRV long terminal repeat (LTR) activity: a binding site for the lung-specific transcription factor HNF-3β and an E-box element in the distal enhancer adjacent to an NF-κB-like binding site. In addition, in vivo footprints were detected in two downstream motifs likely to bind C/EBP and NF-I. Mutational analysis of a JSRV LTR reporter construct (pJS21luc) revealed that the C/EBP binding site is critical for LTR activity, while the putative NF-I binding element is less important; elimination of these sites resulted in 70% and 40% drops in LTR activity, respectively. Electrophoretic mobility shift assays using nuclear extracts from MLE-15 murine Clara cell-derived mtCC1-2 cells with probes corresponding to the NF-I or C/EBP sites revealed several complexes. Antiserum directed against NF-IA, C/EBPα, or C/EBPβ supershifted the corresponding protein-DNA complexes, indicating that these isoforms, which are also important for the expression of several cellular lung-specific genes, may be important for JSRV expression in lung epithelial cells.

Carbon nanoparticle-induced lung epithelial cell proliferation is mediated by receptor-dependent Akt activation

2008 ◽  
Vol 294 (2) ◽  
pp. L358-L367 ◽  
Author(s):  
Klaus Unfried ◽  
Ulrich Sydlik ◽  
Katrin Bierhals ◽  
Alexander Weissenberg ◽  
Josef Abel
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cells ◽  
Carbon Nanoparticles ◽  
Growth Factor Receptor ◽  
Lung Epithelial Cells ◽  
Alveolar Type ◽  
Specific Cell ◽  
Akt Inhibitor ◽  
Signaling Mechanism ◽  
Lung Epithelial

Treatment of lung epithelial cells with different kinds of nano-sized particles leads to cell proliferation. Because bigger particles fail to induce this reaction, it is suggested that the special surface properties, due to the extremely small size of these kinds of materials, is the common principle responsible for this specific cell reaction. Here the activation of the protein kinase B (Akt) signaling cascade by carbon nanoparticles was investigated with regard to its relevance for proliferation. Kinetics and dose-response experiments demonstrated that Akt is specifically activated by nanoparticulate carbon particles in rat alveolar type II epithelial cells as well as in human bronchial epithelial cells. This pathway appeared to be dependent on epidermal growth factor receptor and β1-integrins. The activation of Akt by these receptors is known to be a feature of adhesion-dependent signaling. However, intracellular proteins described in this context (focal adhesion kinase pp125FAK and integrin-linked kinase) were not activated, indicating a specific signaling mechanism. Inhibitor studies demonstrate that nanoparticle-induced proliferation is mediated by phosphoinositide 3-kinases and Akt. Moreover, overexpression of mutant Akt, as well as pretreatment with an Akt inhibitor, reduced nanoparticle-specific ERK1/2 phosphorylation, which is decisive for nanoparticle-induced proliferation. With this report, we describe the activation of a pathway by carbon nanoparticles that was so far known to be triggered by ligand receptor binding or on cell adhesion to extracellular matrix proteins.

scholarly journals Nanostructured Dihydroartemisinin Plus Epirubicin Liposomes Enhance Treatment Efficacy of Breast Cancer by Inducing Autophagy and Apoptosis

Nanomaterials ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. 804 ◽  
Author(s):  
Ying-Jie Hu ◽  
Jing-Ying Zhang ◽  
Qian Luo ◽  
Jia-Rui Xu ◽  
Yan Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Therapeutic Strategy ◽  
Beclin 1 ◽  
Type I ◽  
Programmed Death ◽  
Cancer Tissues

The heterogeneity of breast cancer and the development of drug resistance are the relapse reasons of disease after chemotherapy. To address this issue, a combined therapeutic strategy was developed by building the nanostructured dihydroartemisinin plus epirubicin liposomes. Investigations were performed on human breast cancer cells in vitro and xenografts in nude mice. The results indicated that dihydroartemisinin could significantly enhance the efficacy of epirubicin in killing different breast cancer cells in vitro and in vivo. We found that the combined use of dihydroartemisinin with epirubicin could efficiently inhibit the activity of Bcl-2, facilitate release of Beclin 1, and further activate Bax. Besides, Bax activated apoptosis which led to the type I programmed death of breast cancer cells while Beclin 1 initiated the excessive autophagy that resulted in the type II programmed death of breast cancer cells. In addition, the nanostructured dihydroartemisinin plus epirubicin liposomes prolonged circulation of drugs, and were beneficial for simultaneously delivering drugs into breast cancer tissues. Hence, the nanostructured dihydroartemisinin plus epirubicin liposomes could provide a new therapeutic strategy for treatment of breast cancer.

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