scholarly journals Numb prevents a complete epithelial–mesenchymal transition by modulating Notch signalling

2017 ◽  
Vol 14 (136) ◽  
pp. 20170512 ◽  
Author(s):  
Federico Bocci ◽  
Mohit K. Jolly ◽  
Satyendra C. Tripathi ◽  
Mitzi Aguilar ◽  
Samir M. Hanash ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cluster Formation ◽  
Cell Signalling ◽  
Stability Factor ◽  
Collective Cell Migration ◽  
Mesenchymal Transition ◽  
Cancer Aggressiveness ◽  
Tumour Initiation

Epithelial–mesenchymal transition (EMT) plays key roles during embryonic development, wound healing and cancer metastasis. Cells in a partial EMT or hybrid epithelial/mesenchymal (E/M) phenotype exhibit collective cell migration, forming clusters of circulating tumour cells—the primary drivers of metastasis. Activation of cell–cell signalling pathways such as Notch fosters a partial or complete EMT, yet the mechanisms enabling cluster formation remain poorly understood. Using an integrated computational–experimental approach, we examine the role of Numb—an inhibitor of Notch intercellular signalling—in mediating EMT and clusters formation. We show via an mathematical model that Numb inhibits a full EMT by stabilizing a hybrid E/M phenotype. Consistent with this observation, knockdown of Numb in stable hybrid E/M cells H1975 results in a full EMT, thereby showing that Numb acts as a brake for a full EMT and thus behaves as a ‘phenotypic stability factor' by modulating Notch-driven EMT. By generalizing the mathematical model to a multi-cell level, Numb is predicted to alter the balance of hybrid E/M versus mesenchymal cells in clusters, potentially resulting in a higher tumour-initiation ability. Finally, Numb correlates with a worse survival in multiple independent lung and ovarian cancer datasets, hence confirming its relationship with increased cancer aggressiveness.

scholarly journals Numb prevents a complete EMT by modulating Notch signalling

2017 ◽  
Author(s):  
Federico Bocci ◽  
Mohit Kumar Jolly ◽  
Satyendra C. Tripathi ◽  
Mitzi Aguilar ◽  
Samir M Hanash ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Cancer Metastasis ◽  
Experimental Approach ◽  
Mesenchymal Cells ◽  
Notch Signalling ◽  
Stability Factor ◽  
M Cells ◽  
Mesenchymal Transition ◽  
Cancer Aggressiveness ◽  
Stable Hybrid

AbstractEpithelial-Mesenchymal Transition (EMT) plays key roles during embryonic development, wound healing, and cancer metastasis. Cells in a partial EMT or hybrid epithelial/mesenchymal (E/M) phenotype tend to exhibit collective cell migration, forming clusters of circulating tumour cells – the primary drivers of metastasis. Activation of cell-cell signalling pathways such as Notch fosters a partial or complete EMT, yet the mechanisms enabling cluster formation remain poorly understood. Using an integrated computational-experimental approach, we examine the role of Numb – an inhibitor of Notch intercellular signalling – in mediating EMT and clusters formation of hybrid E/M cells. Knockdown of Numb in stable hybrid E/M cells H1975 results in a full EMT, thereby showing that Numb acts as a brake for a full EMT. Consistent with this observation, we show via a mathematical model that Numb inhibits a full EMT by stabilizing a hybrid E/M phenotype. Thus, Numb can behave as a ‘phenotypic stability factor’ by modulating Notch-driven EMT. By generalizing the mathematical model to a multi-cell level, Numb is predicted to alter the balance of hybrid E/M versus mesenchymal cells in clusters, potentially resulting in a higher tumour-initiation ability. Finally, Numb correlates with a poor survival in multiple independent lung and ovarian cancer datasets, hence confirming its relationship with increased cancer aggressiveness.Major Findings: we adopt an integrative computational-experimental approach to identify that Numb, an inhibitor of Notch signalling, can stabilize a hybrid epithelial/mesenchymal (E/M) phenotype. We show that knockdown of Numb in H1975 cells that display a stable hybrid E/M state is sufficient to destabilize a hybrid E/M state and push them to a full EMT phenotype. Next, we develop a mechanism-based mathematical model that recapitulates this ability of Numb in maintaining a hybrid E/M state, and predicts that Numb can alter the relative frequency of hybrid E/M and mesenchymal cells at a tissue level or in clusters of circulating tumor cells (CTCs) – the primary drivers of metastasis. Finally, we show that across cancer types, Numb correlates with worse patient survival, thus reinforcing the emerging notion that a hybrid E/M, but not necessarily a completely mesenchymal, phenotype associates with elevated tumour progression.

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 NRF2-dependent epigenetic regulation can promote the hybrid epithelial/mesenchymal phenotype

2021 ◽  
Author(s):  
Wen Jia ◽  
Mohit Kumar Jolly ◽  
Herbert Levine
Keyword(s):  
Epigenetic Regulation ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Factor ◽  
Epigenetic Inheritance ◽  
Stability Factor ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Hybrid State ◽  
Regulation Model

AbstractThe epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesehncymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous work has suggested that NRF2 can act as phenotypic stability factor to help stablize such hybrid states. Here, we incorporate a phenomenological epigenetic feedback effect into our previous computational model for EMT signaling. We show that this type of feedback can stabilize the hybrid state as compared to the fully mesenchymal phenotype if NRF2 can influence SNAIL at an epigenetic level, as this link makes transitions out of hybrid state more difficult. However, epigenetic regulation on other NRF2-related links do not significantly change the EMT dynamics. Finally, we considered possible cell division effects in our epigenetic regulation model, and our results indicate that the degree of epigenetic inheritance does not appear to be a critical factor for the hybrid E/M state stabilizing behavior of NRF2.

scholarly journals Dynamics of Phenotypic Heterogeneity Associated with EMT and Stemness during Cancer Progression

2019 ◽  
Vol 8 (10) ◽  
pp. 1542 ◽  
Author(s):  
Mohit Kumar Jolly ◽  
Toni Celià-Terrassa
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Relevant Literature ◽  
Phenotypic Heterogeneity ◽  
State Transitions ◽  
Strong Impact ◽  
Mesenchymal Transition ◽  
Cancer Aggressiveness

Genetic and phenotypic heterogeneity contribute to the generation of diverse tumor cell populations, thus enhancing cancer aggressiveness and therapy resistance. Compared to genetic heterogeneity, a consequence of mutational events, phenotypic heterogeneity arises from dynamic, reversible cell state transitions in response to varying intracellular/extracellular signals. Such phenotypic plasticity enables rapid adaptive responses to various stressful conditions and can have a strong impact on cancer progression. Herein, we have reviewed relevant literature on mechanisms associated with dynamic phenotypic changes and cellular plasticity, such as epithelial–mesenchymal transition (EMT) and cancer stemness, which have been reported to facilitate cancer metastasis. We also discuss how non-cell-autonomous mechanisms such as cell–cell communication can lead to an emergent population-level response in tumors. The molecular mechanisms underlying the complexity of tumor systems are crucial for comprehending cancer progression, and may provide new avenues for designing therapeutic strategies.

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 Expression of E-Cadherin in Epithelial Cancer Cells Increases Cell Motility and Directionality through the Localization of ZO-1 during Collective Cell Migration

2021 ◽  
Vol 8 (5) ◽  
pp. 65
Author(s):  
Song-Yi Park ◽  
Hwanseok Jang ◽  
Seon-Young Kim ◽  
Dasarang Kim ◽  
Yongdoo Park ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cell Contact ◽  
Collective Cell Migration ◽  
Collective Migration ◽  
Ags Cells ◽  
Mesenchymal Transition ◽  
E Cadherin

Collective cell migration of epithelial tumor cells is one of the important factors for elucidating cancer metastasis and developing novel drugs for cancer treatment. Especially, new roles of E-cadherin in cancer migration and metastasis, beyond the epithelial–mesenchymal transition, have recently been unveiled. Here, we quantitatively examined cell motility using micropatterned free edge migration model with E-cadherin re-expressing EC96 cells derived from adenocarcinoma gastric (AGS) cell line. EC96 cells showed increased migration features such as the expansion of cell islands and straightforward movement compared to AGS cells. The function of tight junction proteins known to E-cadherin expression were evaluated for cell migration by knockdown using sh-RNA. Cell migration and straight movement of EC96 cells were reduced by knockdown of ZO-1 and claudin-7, to a lesser degree. Analysis of the migratory activity of boundary cells and inner cells shows that EC96 cell migration was primarily conducted by boundary cells, similar to leader cells in collective migration. Immunofluorescence analysis showed that tight junctions (TJs) of EC96 cells might play important roles in intracellular communication among boundary cells. ZO-1 is localized to the base of protruding lamellipodia and cell contact sites at the rear of cells, indicating that ZO-1 might be important for the interaction between traction and tensile forces. Overall, dynamic regulation of E-cadherin expression and localization by interaction with ZO-1 protein is one of the targets for elucidating the mechanism of collective migration of cancer metastasis.

scholarly journals Transactivation of SOX5 by Brachyury promotes breast cancer bone metastasis

2019 ◽  
Vol 41 (5) ◽  
pp. 551-560 ◽  
Author(s):  
Ming Chen ◽  
Shitao Zou ◽  
Chao He ◽  
Jundong Zhou ◽  
Suoyuan Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Cancer Aggressiveness ◽  
Metastatic Relapse

Abstract The bone marrow has been long known to host a unique environment amenable to colonization by metastasizing tumor cells. Yet, the underlying molecular interactions which give rise to the high incidence of bone metastasis (BM) in breast cancer patients have long remained uncharacterized. In our study, in vitro and in vivo assays demonstrated that Brachyury (Bry) could promote breast cancer BM. Bry drives epithelial–mesenchymal transition (EMT) and promotes breast cancer aggressiveness. As an EMT driver, SOX5 involves in breast cancer metastasis and the specific function in BM. Chromatin immunoprecipitation (ChIP) assays revealed SOX5 is a direct downstream target gene of Bry. ChIP analysis and reporter assays identified two Bry-binding motifs; one consistent with the classic conserved binding sequence and the other a new motif sequence. This study demonstrates for the first time that Bry promotes breast cancer cells BM through activating SOX5. In clinical practice, targeting the Bry-Sox5-EMT pathway is evolving into a promising avenue for the prevention of bone metastatic relapse, therapeutic resistance and other aspects of breast cancer progression. Brachyury directly regulates the expression of SOX5 by binding to two motifs in its promoter region. The Bry-SOX5-EMT pathway may represent a potential target to develop treatments to prevent and treat bone metastasis from breast cancer.

scholarly journals Nrf2 regulates collective cancer migration by modulating the hybrid epithelial/mesenchymal phenotype

2021 ◽  
Author(s):  
Samuel A Vilchez Mercedes ◽  
Federico Bocci ◽  
Ninghao Zhu ◽  
Herbert Levine ◽  
José N Onuchic ◽  
...  
Keyword(s):  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Leading Edge ◽  
Stability Factor ◽  
Phenotypic Stability ◽  
Interior Region ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Cancer Migration ◽  
Aggressive Cancer

AbstractHybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. A challenge is to understand how these cells, which are mostly non-existent in healthy tissue, become stable phenotypes participating collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and resistance to therapy, appears to be central to this process. Here, using a combined experimental-computational approach, we show that Nrf2 functions as a phenotypic stability factor for hybrid E/M cells by inhibiting a complete epithelial-mesenchymal transition (EMT) during collective cancer migration. We demonstrate that Nrf2 and EMT signaling are spatially coordinated near the migrating front. Computational analysis of Nrf2-EMT-Notch network and experimental modulation of Nrf2 by pharmacological treatment and CRISPR/Cas9 gene editing reveal that Nrf2 stabilizes a hybrid E/M phenotype maximally observed in the interior region immediately behind the leading edge. We further demonstrate that the Nrf2-EMT-Notch network enhances Dll4 and Jagged1 expression near the leading edge, which correlates with the formation of protruding tips and leader cells. Together, Nrf2 acts as a phenotypic stability factor in restricting complete EMT and coordinating collective cancer migration.

Epithelial, mesenchymal and hybrid epithelial/mesenchymal phenotypes and their clinical relevance in cancer metastasis

2017 ◽  
Vol 19 ◽  
Author(s):  
Minal Garg
Keyword(s):  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Strong Association ◽  
Experimental Studies ◽  
Tumour Cells ◽  
Cellular Plasticity ◽  
Mesenchymal Transition ◽  
Tumour Initiation ◽  
Regulatory Functions

Cancer metastasis occurs through local invasion of circulating tumour cells (CTCs), intravasation, transportation to distant sites, and their extravasation followed by colonisation at secondary sites. Epithelial–mesenchymal transition (EMT) is a normal developmental phenomenon, but its aberrant activation confers tumour cells with enhanced cell motility, metastatic properties, resistant to therapies and cancer stem cell (CSC) phenotype in epithelium-derived carcinoma.Experimental studies from various research papers have been reviewed to determine the factors, which interlink cancer stemness and cellular plasticity with EMT. Although existence of CSCs has been linked with EMT, nevertheless, there are controversies with the involvement of type of tumour cells, including cells with E (epithelial) and M (mesenchymal) phenotype alone or hybrid E/M phenotype in different types of cancers. Studies on CTCs with hybrid E/M phenotypes during different stages of cancer metastasis reveal strong association with tumour -initiation potential, cellular plasticity and types of cancer cells. Cells with the hybrid E/M state are strictly controlled by phenotypic stability factors coupled to core EMT decision-making circuits, miR200/ZEB and miR-34/Snail.Understanding the regulatory functions of EMT program in cancer metastasis can help us to characterise the biomarkers of prognostic and therapeutic potential. These biomarkers when targeted may act as metastatic suppressors, inhibit cellular plasticity and stemness ability of tumour cells and can block metastatic growth.

scholarly journals NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype

2018 ◽  
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

AbstractThe 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. Here, 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 destabilised 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’.

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