scholarly journals Machine learning reveals mesenchymal breast carcinoma cell adaptation in response to matrix stiffness

2021 ◽  
Vol 17 (7) ◽  
pp. e1009193
Author(s):  
Vlada S. Rozova ◽  
Ayad G. Anwer ◽  
Anna E. Guller ◽  
Hamidreza Aboulkheyr Es ◽  
Zahra Khabir ◽  
...  
Keyword(s):  
Machine Learning ◽  
Breast Carcinoma ◽  
Soft Tissues ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cell ◽  
Primary Tumour ◽  
Cluster Formation ◽  
Mesenchymal Transition ◽  
Organ Microenvironment ◽  
E Cadherin

Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET), are believed to play key roles in facilitating the metastatic cascade. Metastatic lesions often exhibit a similar epithelial-like state to that of the primary tumour, in particular, by forming carcinoma cell clusters via E-cadherin-mediated junctional complexes. However, the factors enabling mesenchymal-like micrometastatic cells to resume growth and reacquire an epithelial phenotype in the target organ microenvironment remain elusive. In this study, we developed a workflow using image-based cell profiling and machine learning to examine morphological, contextual and molecular states of individual breast carcinoma cells (MDA-MB-231). MDA-MB-231 heterogeneous response to the host organ microenvironment was modelled by substrates with controllable stiffness varying from 0.2kPa (soft tissues) to 64kPa (bone tissues). We identified 3 distinct morphological cell types (morphs) varying from compact round-shaped to flattened irregular-shaped cells with lamellipodia, predominantly populating 2-kPa and >16kPa substrates, respectively. These observations were accompanied by significant changes in E-cadherin and vimentin expression. Furthermore, we demonstrate that the bone-mimicking substrate (64kPa) induced multicellular cluster formation accompanied by E-cadherin cell surface localisation. MDA-MB-231 cells responded to different substrate stiffness by morphological adaptation, changes in proliferation rate and cytoskeleton markers, and cluster formation on bone-mimicking substrate. Our results suggest that the stiffest microenvironment can induce MET.

Epithelial-mesenchymal transition and metastatic bladder cancer profile under vinflunine treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22021-e22021
Author(s):  
Angelica Figueroa ◽  
Vanessa Abella ◽  
Guadalupe Aparicio ◽  
Mar Haz-Conde ◽  
Javier Gayo ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Bladder Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cell ◽  
Human Bladder ◽  
Mesenchymal Transition ◽  
Carcinoma Cell Lines ◽  
Emt Markers ◽  
E Cadherin

e22021 Background: Given the role of vinflunine (VFL) in the microtubule dynamics and the link between microtubules and cell adhesions through cadherins, we have investigated the possible influence of VFL on adherens junctions through its interaction with microtubules. We have studied the implication of VFL on the reversion of epithelial-mesenchymal transition (EMT) in bladder transitional cell carcinoma and explored a possible novel molecular mechanism. Methods: Four human bladder transitional carcinoma cell lines were used to carry out the following experimental procedure: Cytotoxicity assay by using MTT assay, qRTPCR to analyze mRNA markers of the EMT, Western blotting using specific antibodies for EMT markers, and immunofluorescence images, analyzed by epifluorescence microscopy. Results: Cell growth reduction was detected in human bladder carcinoma cells under VFL treatment compared to control. VFL induces mesenchymal to epithelial phenotype and modulates the EMT markers: E-cadherin and Cytokeratin-19 were enhanced under treatment, while significantly reduction of mRNA mesenchymal markers expression (Vimentin, N-cadherin) and EMT-transcriptional factors (Snail and Zeb1) was detected. Strong reduction of Hakai protein was seen under VFL treatment. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin. Epifluorescence images showed that VFL treatment promotes E-cadherin localization specifically at cell-cell contact; while, Hakai expression decreases its expression in the nuclei and cytoplasm. Conclusions: These results suggest that VFL up-regulates E-cadherin contributing to mesenchymal to epithelial transition, and that Hakai modulation might be the molecular mechanism by which the increasing E-cadherin at cell-cell contacts in bladder carcinoma cell lines is detected. Given the relevant in vitro role of VFL on E-cadherin expression and on the reversion of EMT process, we hypothesized that VFL could exert a clinical benefit in delaying the metastasis in urothelial tumors.

scholarly journals Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5118
Author(s):  
Hamidreza Aboulkheyr Es ◽  
Thomas R Cox ◽  
Ehsan Sarafraz-Yazdi ◽  
Jean Paul Thiery ◽  
Majid Ebrahimi Warkiani
Keyword(s):  
Breast Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cell ◽  
Positive Association ◽  
Carcinoma Cells ◽  
The Cancer Genome Atlas ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancer Patients ◽  
Spheroid Formation ◽  
Mesenchymal Transition

The aim of this study was to assess the effects of pirfenidone (PFD) on promoting epithelial–mesenchymal-transition (EMT) and stemness features in breast carcinoma cells through targeting cancer-associated-fibroblasts (CAFs). Using The Cancer Genome Atlas (TCGA) database, we analyzed the association between stromal index, EMT, and stemness-related genes across 1084 breast cancer patients, identifying positive correlation between YAP1, EMT, and stemness genes in samples with a high-stromal index. We monitored carcinoma cell invasion and spheroid formation co-cultured with CAFs in a 3D microfluidic device, followed by exposing carcinoma cells, spheroids, and CAFs with PFD. We depicted a positive association between the high-stromal index and the expression of EMT and stemness genes. High YAP1 expression in samples correlated with more advanced EMT status and stromal index. Additionally, we found that CAFs promoted spheroid formation and induced the expression of YAP1, VIM, and CD44 in spheroids. Treatment with PFD reduced carcinoma cell migration and decreased the expression of these genes at the protein level. The cytokine profiling showed significant depletion of various EMT- and stemness-regulated cytokines, particularly IL8, CCL17, and TNF-beta. These data highlight the potential application of PFD on inhibiting EMT and stemness in carcinoma cells through the targeting of critical cytokines.

scholarly journals ABCG2/BCRP gene expression is related to epithelial–mesenchymal transition inducer genes in a papillary thyroid carcinoma cell line (TPC-1)

2014 ◽  
Vol 52 (3) ◽  
pp. 289-300 ◽  
Author(s):  
E Mato ◽  
C González ◽  
A Moral ◽  
J I Pérez ◽  
O Bell ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Cell Line ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cell ◽  
Thyroid Tumor ◽  
Carcinoma Cell Line ◽  
Human Thyroid ◽  
Mesenchymal Transition ◽  
Starting Point ◽  
E Cadherin

Tumor malignancy is associated with the epithelial–mesenchymal transition (EMT) process and resistance to chemotherapy. However, little is known about the relationship between the EMT and the multidrug-resistance gene in thyroid tumor progression. We investigated whether the expression of theABCG2/BCRPgene is associated withZEB1and other EMT inducer genes involved in tumor dedifferentiation. We established a subpopulation of cells that express theABCG2/BCRPgene derived from the thyroid papillary carcinoma cell line (TPC-1), the so-called TPC-1 MITO-resistant subline. The most relevant findings in these TPC-1 selected cells were a statistically significant upregulation ofZEB1andTWIST1(35- and 15-fold change respectively), no changes in the relative expression of vimentin andSNAIL1, and no expression of E-cadherin. The TPC-1 MITO-resistant subline displayed a faster migration and greater invasive ability than parental cells in correlation with a significant upregulation of the survivin (BIRC5) gene (twofold change,P<0.05). The knockdown ofZEB1promoted nuclear re-expression of E-cadherin, reduced expression of vimentin, N-cadherin, andBIRC5genes, and reduced cell migration (P<0.05). Analysis of human thyroid carcinoma showed a slight overexpression of theABCG2/BCRPat stages I and II (P<0.01), and a higher overexpression at stages III and IV (P<0.01).SNAIL1,TWIST1, andZEB1genes showed higher expression at stages III and IV than at stages I and II. E- and N-cadherin genes were upregulated at stages I and II of the disease (ninefold and tenfold change, respectively,P<0.01) but downregulated at stages III and IV (fourfold lower,P<0.01). These results could be a promising starting point for further study of the role of theABCG2/BCRPgene in the progression of thyroid tumor.

scholarly journals ID1 mediates resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer through epithelial–mesenchymal transition

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kejun Liu ◽  
Xianwen Chen ◽  
Ligang Wu ◽  
Shiyuan Chen ◽  
Nianxin Fang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Epithelial Mesenchymal Transition ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Egfr T790m ◽  
E Cadherin

Abstract Background ID1 is associated with resistance to the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, the effect of ID1 expression on osimertinib resistance in EGFR T790M-positive NSCLC is not clear. Methods We established a drug-resistant cell line, H1975/OR, from the osimertinib-sensitive cell line H1975. Alterations in ID1 protein expression and Epithelial–mesenchymal transition (EMT)-related proteins were detected with western blot analysis. RT-PCR was used to evaluate the differences of gene mRNA levels. ID1 silencing and overexpression were used to investigate the effects of related gene on osimertinib resistance. Cell Counting Kit-8 (CCK8) was used to assess the proliferation rate in cells with altered of ID1 expression. Transwell assay was used to evaluate the invasion ability of different cells. The effects on the cell cycle and apoptosis were also compared using flow cytometry. Results In our study, we found that in osimertinib-resistant NSCLC cells, the expression level of the EMT-related protein E-cadherin was lower than that of sensitive cells, while the expression level of ID1 and vimentin were higher than those of sensitive cells. ID1 expression levels was closely related to E-cadherin and vimentin in both osimertinib-sensitive and resistant cells. Alteration of ID1 expression in H1975/OR cells could change the expression of E-cadherin. Downregulating ID1 expression in H1975/OR cells could inhibit cell proliferation, reduce cell invasion, promote cell apoptosis and arrested the cell cycle in the G1/G0 stage phase. Our study suggests that ID1 may induce EMT in EGFR T790M-positive NSCLC, which mediates drug resistance of osimertinib. Conclusions Our study revealed the mechanism of ID1 mediated resistance to osimertinib in EGFR T790M-positive NSCLC through EMT, which may provide new ideas and methods for the treatment of EGFR mutated NSCLC after osimertinib resistance.

scholarly journals Distinct Ring1b complexes defined by DEAD-box helicases and EMT transcription factors synergistically enhance E-cadherin silencing in breast cancer

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yawei Wang ◽  
Yingying Sun ◽  
Chao Shang ◽  
Lili Chen ◽  
Hongyu Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factors ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Mechanism ◽  
Regulation Mechanism ◽  
Rna Helicases ◽  
Mesenchymal Transition ◽  
Dead Box ◽  
E Cadherin

AbstractRing1b is a core subunit of polycomb repressive complex 1 (PRC1) and is essential in several high-risk cancers. However, the epigenetic mechanism of Ring1b underlying breast cancer malignancy is poorly understood. In this study, we showed increased expression of Ring1b promoted metastasis by weakening cell–cell adhesions of breast cancer cells. We confirmed that Ring1b could downregulate E-cadherin and contributed to an epigenetic rewiring via PRC1-dependent function by forming distinct complexes with DEAD-box RNA helicases (DDXs) or epithelial-mesenchymal transition transcription factors (EMT TFs) on site-specific loci of E-cadherin promoter. DDXs-Ring1b complexes moderately inhibited E-cadherin, which resulted in an early hybrid EMT state of epithelial cells, and EMT TFs-Ring1b complexes cooperated with DDXs-Ring1b complexes to further repress E-cadherin in mesenchymal-like cancer cells. Clinically, high expression of Ring1b with DDXs or EMT TFs predicted low levels of E-cadherin, metastatic behavior, and poor prognosis. These findings provide an epigenetic regulation mechanism of Ring1b complexes in E-cadherin expression. Ring1b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer.

scholarly journals Absence of EpCAM in cervical cancer cells is involved in slug induced epithelial-mesenchymal transition

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xian Liu ◽  
Qian Feng ◽  
Yanru Zhang ◽  
PengSheng Zheng ◽  
Nan Cui
Keyword(s):  
Cervical Cancer ◽  
Cell Motility ◽  
Cancer Cells ◽  
Negative Correlation ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Suppression Effect ◽  
Epcam Expression ◽  
Cervical Cancer Cells ◽  
E Cadherin

Abstract Background Slug (Snai2) is a pivotal player in initiating epithelial-mesenchymal transition (EMT) through its trans-suppression effect on E-cadherin in various normal and malignant cells. In this study, the positive effect of Slug on promoting cell motility and metastasis in cervical cancer was further confirmed in this study. Methods RNA-Seq was performed to explore the potential molecules that participate in Slug-mediated EMT in cervical cancer cells. The negative correlation between Slug and EpCAM expression in cervical cancer cells was detected in this study, and linked them with in vitro migration and invasion assay, in vivo metastasis experiments, luciferase reporter assay and Chromatin immunoprecipitation. Results Transcriptome sequencing analysis revealed that epithelial cell adhesion molecule (EpCAM) was significantly decreased in Slug-overexpressing SiHa cells. Simultaneously, an absence of EpCAM expression was observed in Slug-overexpressing cells. Further studies revealed the trans-suppression effect of Slug on EpCAM through its binding to the E-boxes in the proximal promoter region of EpCAM in cervical cancer cells. Restoring EpCAM in Slug-overexpressing cells by transiently transfecting an EpCAM recombinant plasmid attenuated cell motility and promoted cell growth. Moreover, the negative correlation between Slug and EpCAM expression in human squamous cervical carcinoma (SCC) samples was verified by using Pearson correlation analysis. Conclusions These results demonstrated that the absence of EpCAM under Slug expression in cervical cancer cells probably participated in Slug-regulated EMT and further promoted tumor metastasis. Additionally, this study supports a potential way for Slug to initiate EMT progression in cervical cancer cells in addition to inhibiting E-cadherin.

scholarly journals Epithelial-Mesenchymal Transition Phenotype, Metformin, and Survival for Colorectal Cancer Patients with Diabetes Mellitus II

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Yaodu Wang ◽  
Zhiyang Wu ◽  
Likuan Hu
Keyword(s):  
Diabetes Mellitus ◽  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Disease Free Survival ◽  
Multivariate Regression Analysis ◽  
Stage I ◽  
Clinicopathological Parameters ◽  
Mesenchymal Transition ◽  
Patients With Diabetes ◽  
E Cadherin

Objectives. We aimed to explore the association between metformin treatment and epithelial-mesenchymal transition (EMT) phenotype and further appraise the prognostic values of metformin and EMT markers E-cadherin and vimentin for colorectal cancer (CRC) in clinical practice. Methods. We collected specimens and evaluated clinicopathological parameters of 102 stage I to III CRC patients with prediagnosed type 2 diabetes mellitus (DM II). Expression of E-cadherin and vimentin in tumors was detected by immunohistochemistry (IHC), and statistical analysis was performed using SPSS 19.0. Results. In correlation tests, we found a lower tumor cell EMT degree (more E-cadherin (P=0.014) and less vimentin (P=0.011) expression in patients who used metformin, and the expression of E-cadherin and vimentin was associated with serum CA19-9 (P=0.048, P=0.009), tumor invasive depth (T) (P<0.001, P=0.045), and lymph invasion (N) (P=0.013, P=0.001). In Cox multivariate regression analysis, E-cadherin was identified as a prognostic factor for disease-free survival (DFS) (P=0.038) and metformin use (P=0.015P=0.044) and lymph invasion (P=0.016P=0.023) were considered as the prognostic factors for both DFS and overall survival (OS). Conclusion. Our study suggested that metformin may impede the EMT process and improve survival for stage I–III CRC patients with DM II.

The Impacts of Bone Marrow Mesenchymal Stem Cells (BMSCs)-Derived Periostin on Epithelial-Mesenchymal Transition (EMT) of Cervical Cancer Cells

2022 ◽  
Vol 12 (4) ◽  
pp. 820-826
Author(s):  
Chengyong Wu ◽  
Weifeng Wei ◽  
Jing Li ◽  
Shenglin Peng
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Signal Transduction Pathway ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Essential Components ◽  
Cervical Cancer Cells ◽  
E Cadherin

Epithelial-mesenchymal transition (EMT) is closely related to the migrating and invading behaviors of cells. Periostin is one of the essential components in the extracellular matrix and can induce EMT of cells and their sequential metastasis. But its underlying mechanism is unclear. The Hela and BMSC cell lines were assigned into Periostin-mimic group, Periostin-Inhibitor group and Periostin-NC group followed by analysis of cell migration and invasion, expression of E-Cadherin, Vimentin, β-Catenin, Snail, MMP-2, MMP-9, PTEN, and p-PTEN. Cells in Periostin-mimic group exhibited lowest migration, least number of invaded cells, as well as lowest levels of Vimentin, β-Catenin, Snail, MMP-2, MMP-9, p-PTEN, Akt, p-Akt, p-GSK-3β, p-PDK1 and p-cRcf, along with highest levels of E-cadherin and PTEN. Moreover, cells in Periostin-NC group had intermediate levels of these above indicators, while, the Periostin-Inhibitor group exhibited the highest migration rate, the most number of invaded cells, and the highest levels of these proteins (P < 0.05). In conclusion, BMSCs-derived Periostin can influence the EMT of cervical cancer cells possibly through restraining the activity of the PI3K/AKT signal transduction pathway, indicating that Periostin might be a target of chemotherapy in clinics for the treatment of cervical cancer.

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