Biophysical and biochemical attributes of hybrid epithelial/mesenchymal phenotypes

2022 ◽  
Author(s):  
Ayalur Raghu Subbalakshmi ◽  
Bazella Ashraf ◽  
Mohit Kumar Jolly
Keyword(s):  
Patient Outcomes ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Epithelial Mesenchymal Transition ◽  
Collective Cell Migration ◽  
Hybrid Cells ◽  
Biological Phenomenon ◽  
Mesenchymal Transition ◽  
Binary Process ◽  
Made In

Abstract The Epithelial-Mesenchymal Transition (EMT) is a biological phenomenon associated with explicit phenotypic and molecular changes in cellular traits. Unlike the earlier-held popular belief of it being a binary process, EMT is now thought of as a landscape including diverse hybrid E/M phenotypes manifested by varying degrees of the transition. These hybrid cells can co-express both epithelial and mesenchymal markers and/or functional traits, and can possess the property of collective cell migration, enhanced tumor-initiating ability, and immune/targeted therapy-evasive features, all of which are often associated with worse patient outcomes. These characteristics of the hybrid E/M cells have led to a surge in studies that map their biophysical and biochemical hallmarks that can be helpful in exploiting their therapeutic vulnerabilities. This review discusses recent advances made in investigating hybrid E/M phenotype(s) from diverse biophysical and biochemical aspects by integrating live cell-imaging, cellular morphology quantification and mathematical modelling, and highlights a set of questions that remain unanswered about the dynamics of hybrid E/M states.

scholarly journals Biophysical and Biochemical Attributes of Hybrid Epithelial/Mesenchymal Phenotypes

2021 ◽  
Author(s):  
Subbalakshmi Ayalur Raghu ◽  
Bazella Ashraf ◽  
Mohit Kumar Jolly
Keyword(s):  
Patient Outcomes ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Epithelial Mesenchymal Transition ◽  
Collective Cell Migration ◽  
Hybrid Cells ◽  
Biological Phenomenon ◽  
Mesenchymal Transition ◽  
Binary Process ◽  
Made In

The Epithelial- Mesenchymal Transition (EMT) is a biological phenomenon associated with explicit phenotypic and molecular changes in cellular traits. Unlike the earlier-held popular belief of it being a binary process, EMT is now thought of as a landscape including diverse hybrid E/M phenotypes manifested by varying degrees of the transition. These hybrid cells can co-express both epithelial and mesenchymal markers and/or functional traits, and can possess the property of collective cell migration, enhanced tumor-initiating ability, and immune/targeted therapy-evasive features, all of which are often associated with worse patient outcomes. These characteristics of the hybrid E/M cells have led to a surge in studies that map their biophysical and biochemical hallmarks that can be helpful in exploiting their therapeutic vulnerabilities. This review discusses recent advances made in investigating hybrid E/M phenotype(s) from diverse biophysical and biochemical aspects by integrating live cell-imaging, cellular morphology quantification and mathematical modeling, and highlights a set of questions that remain unanswered about the dynamics of hybrid E/M states.

scholarly journals BMP4-induced symmetry breaking in a 3D model of the human epiblast

2019 ◽  
Author(s):  
Mijo Simunovic ◽  
Ali H. Brivanlou ◽  
Eric D. Siggia
Keyword(s):  
Live Cell Imaging ◽  
3D Model ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Imaging ◽  
Embryonic Stem ◽  
Primitive Streak ◽  
Mesenchymal Transition ◽  
Pluripotency Markers ◽  
Anterior Posterior

Abstract We describe the protocol of generating a 3D stem-cell-based model of the human pre-gastrulation epiblast by culturing human embryonic stem cells in a mix of hydrogel and Matrigel. Much like the epiblast of an in vitro attached day-10 human embryo, this model is an epithelial sphere with a cavity at its center, it is expressing key pluripotency markers, and it displays apico-basal polarity. The 3D colonies can further be differentiated with morphogens and in the case of intermediate concentrations of BMP4, they break the anterior-posterior symmetry characterized by an asymmetric expression of a primitive streak marker and showing signs of epithelial to mesenchymal transition. The protocol described here is suitable for immunofluorescence staining and for live-cell imaging.

scholarly journals Cripto-1 Promotes the Epithelial-Mesenchymal Transition in Esophageal Squamous Cell Carcinoma Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Chun Huang ◽  
Wangsheng Chen ◽  
Xiaowen Wang ◽  
Jinqiu Zhao ◽  
Qian Li ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Public Health Problem ◽  
Carcinoma Cells ◽  
Malignant Neoplasms ◽  
Major Public Health Problem ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Tumorigenesis And Progression ◽  
Made In

Esophageal carcinoma is a major public health problem worldwide and one of the most aggressively malignant neoplasms. Although considerable diagnostic and therapeutic progress has been made in recent years, the prognosis of EC patients still remains dismal due to high rates of recurrence/metastasis and invasion. Previous studies have demonstrated that Epithelial mesenchymal transition (EMT) is proposed as a critical mechanism for the acquisition of malignant phenotypes by epithelial cells. Several lines of evidence have shown that Cripto-1 plays an important oncogenic role during tumorigenesis by promoting EMT. The aim of our study was to evaluate the significance of Cripto-1 which plays a role in EMT and its metastasis in esophageal carcinoma. Data of this study suggest that Cripto-1 overexpression is connected with the tumorigenesis and progression of esophageal carcinoma; shRNA might be feasible for the inhibition of the invasion and metastasis of esophageal carcinoma.

scholarly journals NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype

2019 ◽  
Vol 11 (6) ◽  
pp. 251-263 ◽  
Author(s):  
Federico Bocci ◽  
Satyendra C Tripathi ◽  
Samuel A Vilchez Mercedes ◽  
Jason T George ◽  
Julian P Casabar ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Collective Cell Migration ◽  
Mesenchymal Transition ◽  
Regulatory Circuit ◽  
Clinical Records ◽  
E Cadherin

Abstract The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype – a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) – the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the ‘metastatic sweet spot’.

scholarly journals CARMIL2 is a novel molecular connection between vimentin and actin essential for cell migration and invadopodia formation

2015 ◽  
Vol 26 (25) ◽  
pp. 4577-4588 ◽  
Author(s):  
M. Hunter Lanier ◽  
Taekyung Kim ◽  
John A. Cooper
Keyword(s):  
Cell Migration ◽  
Epithelial Mesenchymal Transition ◽  
Collective Cell Migration ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Membrane Ruffling ◽  
Capping Protein ◽  
Actin Capping Protein ◽  
Invadopodia Formation ◽  
Vimentin Filaments

Cancer cell migration requires the regulation of actin networks at protrusions associated with invadopodia and other leading edges. Carcinomas become invasive after undergoing an epithelial–mesenchymal transition characterized by the appearance of vimentin filaments. While vimentin expression correlates with cell migration, the molecular connections between vimentin- and actin-based membrane protrusions are not understood. We report here that CARMIL2 (capping protein, Arp2/3, myosin-I linker 2) provides such a molecular link. CARMIL2 localizes to vimentin, regulates actin capping protein (CP), and binds to membranes. CARMIL2 is necessary for invadopodia formation, as well as cell polarity, lamellipodial assembly, membrane ruffling, macropinocytosis, and collective cell migration. Using point mutants and chimeras with defined biochemical and cellular properties, we discovered that localization to vimentin and CP binding are both essential for the function of CARMIL2 in cells. On the basis of these results, we propose a model in which dynamic vimentin filaments target CARMIL2 to critical membrane-associated locations, where CARMIL2 regulates CP, and thus actin assembly, to create cell protrusions.

scholarly journals Hypoxia, Partial EMT and Collective Migration: Emerging Culprits in Metastasis

2020 ◽  
Author(s):  
Kritika Saxena ◽  
Mohit Kumar Jolly ◽  
Kuppusamy Balamurugan
Keyword(s):  
Drug Resistance ◽  
Cell Migration ◽  
Epithelial Mesenchymal Transition ◽  
Biological Process ◽  
Collective Cell Migration ◽  
Collective Migration ◽  
Mesenchymal Transition ◽  
Cancer Aggressiveness ◽  
Migration Of Cells ◽  
Successful Colonization

Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the ‘fittest’ for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1α can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1α and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.

scholarly journals In vivo collective cell migration requires an LPAR2-dependent increase in tissue fluidity

2014 ◽  
Vol 206 (1) ◽  
pp. 113-127 ◽  
Author(s):  
Sei Kuriyama ◽  
Eric Theveneau ◽  
Alexandre Benedetto ◽  
Maddy Parsons ◽  
Masamitsu Tanaka ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Mesenchymal Transition ◽  
Intermediate Phenotype ◽  
Collective Cell Migration ◽  
Embryonic Cells ◽  
Lpa Receptor ◽  
Mesenchymal Transition ◽  
Physical Constraints ◽  
Cell Cell

Collective cell migration (CCM) and epithelial–mesenchymal transition (EMT) are common to cancer and morphogenesis, and are often considered to be mutually exclusive in spite of the fact that many cancer and embryonic cells that have gone through EMT still cooperate to migrate collectively. Here we use neural crest (NC) cells to address the question of how cells that have down-regulated cell–cell adhesions can migrate collectively. NC cell dissociation relies on a qualitative and quantitative change of the cadherin repertoire. We found that the level of cell–cell adhesion is precisely regulated by internalization of N-cadherin downstream of lysophosphatidic acid (LPA) receptor 2. Rather than promoting the generation of single, fully mesenchymal cells, this reduction of membrane N-cadherin only triggers a partial mesenchymal phenotype. This intermediate phenotype is characterized by an increase in tissue fluidity akin to a solid-like–to–fluid-like transition. This change of plasticity allows cells to migrate under physical constraints without abolishing cell cooperation required for collectiveness.

scholarly journals Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3708
Author(s):  
Inés Sáenz-de-Santa-María ◽  
Lucía Celada ◽  
Andrés San José Martínez ◽  
Tamara Cubiella ◽  
María-Dolores Chiara
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Squamous Cell ◽  
Epithelial Mesenchymal Transition ◽  
Collective Cell Migration ◽  
Mesenchymal Transition ◽  
Squamous Cancer ◽  
Cancer Dissemination

Metastasis remains a clinically unsolved issue in cancer that is initiated by the acquisition of collective migratory properties of cancer cells. Phenotypic and functional heterogeneity that arise among cancer cells within the same tumor increase cellular plasticity and promote metastasis, however, their impact on collective cell migration is incompletely understood. Here, we show that in vitro collective cancer cell migration depends on FAK and MMP-2 and on the presence of cancer-associated fibroblasts (CAFs). The absence of functional FAK rendered cancer cells incapable of invading the surrounding stroma. However, CAFs and cancer cells over-expressing MMP-2 released FAK-deficient cells from this constraint by taking the leader positions in the invasive tracks, pushing FAK-deficient squamous cell carcinoma (SCC) cells towards the stroma and leading to the transformation of non-invasive cells into invasive cells. Our cell-based studies and the RNAseq data from the TCGA cohort of patients with head and neck squamous cell carcinomas reveal that, although both FAK and MMP-2 over-expression are associated with epithelial–mesenchymal transition, it is only MMP-2, not FAK, that functions as an independent prognostic factor. Given the significant role of MMP-2 in cancer dissemination, targeting of this molecule, better than FAK, presents a more promising opportunity to block metastasis.

scholarly journals Clinically relevant molecular subtypes and genomic alteration-independent differentiation in gynecologic carcinosarcoma

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Osamu Gotoh ◽  
Yuko Sugiyama ◽  
Yutaka Takazawa ◽  
Kazuyoshi Kato ◽  
Norio Tanaka ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Copy Number ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Subtypes ◽  
Therapeutic Strategies ◽  
Clinicopathological Features ◽  
Genomic Alteration ◽  
Driver Genes ◽  
Mesenchymal Transition ◽  
Genomic Studies

Abstract Carcinosarcoma (CS) of the uterus or ovary is a rare, aggressive and biphasic neoplasm composed of carcinoma and sarcoma elements. Previous genomic studies have identified the driver genes and genomic properties associated with CS. However, there is still no molecular subtyping scheme with clinical relevance for this disease. Here, we sequence 109 CS samples, focusing on 596 genes. We identify four molecular subtypes that resemble those observed in endometrial carcinoma: POLE-mutated, microsatellite instability, copy number high, and copy number low subtypes. These molecular subtypes are linked with DNA repair deficiencies, potential therapeutic strategies, and multiple clinicopathological features, including patient outcomes. Multi-regional comparative sequencing reveals genomic alteration-independent CS cell differentiation. Transcriptome and DNA methylome analyses confirm epithelial-mesenchymal transition as a mechanism of sarcoma differentiation. The current study thus provides therapeutic possibilities for CS as well as clues to understanding the molecular histogenic mechanism of its development.

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