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.

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 Immunosuppressive traits of the hybrid epithelial/mesenchymal phenotype

2021 ◽  
Author(s):  
Sarthak Sahoo ◽  
Sonali Priyadarshini Nayak ◽  
Kishore Hari ◽  
Susmita Mandal ◽  
Akash Kishore ◽  
...  
Keyword(s):  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Causal Link ◽  
M Cells ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
Secondary Tumour

Cancer metastasis remains a primary cause of cancer related mortality. Recent in vitro and in vivo data has indicated the high metastatic fitness of hybrid epithelial/mesenchymal (E/M) states, i.e. their enhanced abilities to initiate tumours at secondary tumour site. Mechanistic details about how such hybrid E/M cells survive the metastatic cascade remain unclear. Here, we investigate immune-evasive strategies of hybrid E/M states, an issue that to date has been largely unexplored. We construct a minimalistic regulatory network that captures known associations between regulators of EMT (the epithelial mesenchymal transition) and levels of PD-L1, an established suppressor of immune response, and simulated the network's emergent dynamics. Our model recapitulates observations that cells undergoing EMT have increased PD-L1 levels, while reverting EMT can decrease these levels, indicative of a causal link between EMT drivers and PD-L1. Further, we show that hybrid E/M cells can have high levels of PD-L1, similar to those seen in cells with a full EMT phenotype, thus obviating the need for cancer cells to undergo a full EMT to evade the immune system. Finally, we identify various signalling pathways and cellular processes that can independently or in concert affect PD-L1 levels and EMT status. For instance, hybrid E/M cells can gain both immune-evasion and stemness through largely independent paths. Our results underscore another underlying reason for the high metastatic ability of hybrid E/M cells.

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 Systems biology approach suggests new miRNAs as phenotypic stability factors in the epithelial–mesenchymal transition

2020 ◽  
Vol 17 (171) ◽  
pp. 20200693
Author(s):  
Daner A. Silveira ◽  
Shantanu Gupta ◽  
José Carlos M. Mombach
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Dose Dependence ◽  
Stability Factor ◽  
Phenotypic Stability ◽  
Mesenchymal Transition ◽  
Hybrid State ◽  
Breast Cells ◽  
Mcf10a Cells ◽  
Phenotypic Transition ◽  
Autocrine Mechanism

The epithelial–mesenchymal transition (EMT) is a cellular programme on which epithelial cells undergo a phenotypic transition to mesenchymal ones acquiring metastatic properties such as mobility and invasion. TGF-β signalling can promote the EMT process. However, the dynamics of the concentration response of TGF-β-induced EMT is not well explained. In this work, we propose a logical model of TGF-β dose dependence of EMT in MCF10A breast cells. The model outcomes agree with experimentally observed phenotypes for the wild-type and perturbed/mutated cases. As important findings of the model, it predicts the coexistence of more than one hybrid state and that the circuit between TWIST1 and miR-129 is involved in their stabilization. Thus, miR-129 should be considered as a phenotypic stability factor. The circuit TWIST1/miR-129 associates with ZEB1-mediated circuits involving miRNAs 200, 1199, 340, and the protein GRHL2 to stabilize the hybrid state. Additionally, we found a possible new autocrine mechanism composed of the circuit involving TGF-β, miR-200, and SNAIL1 that contributes to the stabilization of the mesenchymal state. Therefore, our work can extend our comprehension of TGF-β-induced EMT in MCF10A cells to potentially improve the strategies for breast cancer treatment.

scholarly journals Comprehensive profiling of novel epithelial–mesenchymal transition mediators and their clinical significance in colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Satoshi Ishikawa ◽  
Naohiro Nishida ◽  
Shiki Fujino ◽  
Takayuki Ogino ◽  
Hidekazu Takahashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Gene Signature ◽  
Clinical Samples ◽  
Phenotypic Change ◽  
Mesenchymal Transition ◽  
Aggressive Cancer ◽  
Neuronal Gene ◽  
Functional Alteration

AbstractEpithelial–mesenchymal transition (EMT) is a drastic phenotypic change during cancer metastasis and is one of the most important hallmarks of aggressive cancer. Although the overexpression of some specific transcription factors explains the functional alteration of EMT-induced cells, a complete picture of this biological process is yet to be elucidated. To comprehensively profile EMT-related genes in colorectal cancer, we quantified the EMT induction ability of each gene according to its similarity to the cancer stromal gene signature and termed it “mesenchymal score.” This bioinformatic approach successfully identified 90 candidate EMT mediators, which are strongly predictive of survival in clinical samples. Among these candidates, we discovered that the neuronal gene ARC, possibly originating from the retrotransposon, unexpectedly plays a crucial role in EMT induction. Profiling of novel EMT mediators we demonstrated here may help understand the complexity of the EMT program and open up new avenues for therapeutic intervention in colorectal cancer.

scholarly journals Anti-invasion and anti-proliferation effects of 3-acetyl-5,8-dichloro-2-((2,4-di-chlorophenyl)amino)quinolin-4(1H)-one (ADQ) via regulation of Akt and Twist1 in liver cancer cells

2020 ◽  
Author(s):  
Jain Ha ◽  
Sewoong Lee ◽  
Jiyoung Park ◽  
Jihye Seo ◽  
Eunjeong Kang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Drug ◽  
Multicellular Tumor Spheroid ◽  
Carcinogenic Activity ◽  
Mesenchymal Transition ◽  
Cellular Invasion ◽  
Aggressive Cancer ◽  
Limited Oxygen

Abstract When primary cancer faces limited oxygen and nutrient supply, it undergoes an epithelial-mesenchymal transition, which increases cancer cell motility and invasiveness. The migratory and invasive cancer cells often exert aggressive cancer development or even cancer metastasis. In this study, we investigated a novel compound, 3-acetyl-5,8-dichloro-2-((2,4-dichlorophenyl)amino)quinolin-4(1H)-one (ADQ), that showed significant suppression of wound healing and cellular invasion. This compound also inhibited anchorage-independent cell growth, multicellular tumor spheroid survival/invasion, and metalloprotease activities. The anti-proliferative effects of ADQ were mediated by inhibition of the Akt pathway. In addition, ADQ reduced the expression of mesenchymal markers of cancer cells, which was associated with the suppressed expression of Twist1. In conclusion, ADQ successfully suppressed carcinogenic activity by inhibiting the Akt signaling pathway and Twist1, which suggests that ADQ may be an efficient candidate for cancer drug development.

scholarly journals NFATc acts as a non-canonical phenotypic stability factor for a hybrid epithelial/mesenchymal phenotype

2020 ◽  
Author(s):  
Ayalur Raghu Subbalakshmi ◽  
Deepali Kundnani ◽  
Kuheli Biswas ◽  
Anandamohan Ghosh ◽  
Samir M Hanash ◽  
...  
Keyword(s):  
Phenotypic Plasticity ◽  
Regulatory Networks ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Stochastic Simulations ◽  
Stability Factor ◽  
Dependent Manner ◽  
Phenotypic Stability ◽  
Mesenchymal Transition ◽  
Reversible Transitions

AbstractMetastasis remains the cause of over 90% of cancer-related deaths. Cells undergoing metastasis use phenotypic plasticity to adapt to their changing environmental conditions and avoid therapy and immune response. Reversible transitions between epithelial and mesenchymal phenotypes - Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-Epithelial Transition (MET) - form a key axis of phenotypic plasticity during metastasis and therapy resistance. Recent studies have shown that the cells undergoing EMT/MET can attain one or more hybrid epithelial/mesenchymal (E/M) phenotypes, the process of which is termed as partial EMT/MET. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either epithelial or mesenchymal state. Thus, it is crucial to identify the factors and regulatory networks enabling such hybrid E/M phenotypes. Here, employing an integrated computational-experimental approach, we show that the transcription factor NFATc can inhibit the process of complete EMT, thus stabilizing the hybrid E/M phenotype. It increases the range of parameters enabling the existence of a hybrid E/M phenotype, thus behaving as a phenotypic stability factor (PSF). However, unlike previously identified PSFs, it does not increase the mean residence time of the cells in hybrid E/M phenotypes, as shown by stochastic simulations; rather it enables the co-existence of epithelial, mesenchymal and hybrid E/M phenotypes and transitions among them. Clinical data suggests the effect of NFATc on patient survival in a tissue-specific or context-dependent manner. Together, our results indicate that NFATc behaves as a non-canonical phenotypic stability factor for a hybrid E/M phenotype.

scholarly journals Identification of a novel inhibitor of liver cancer cell invasion and proliferation through regulation of Akt and Twist1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jain Ha ◽  
Sewoong Lee ◽  
Jiyoung Park ◽  
Jihye Seo ◽  
Eunjeong Kang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Drug ◽  
Multicellular Tumor Spheroid ◽  
Carcinogenic Activity ◽  
Mesenchymal Transition ◽  
Cellular Invasion ◽  
Aggressive Cancer

AbstractWhen primary cancer faces limited oxygen and nutrient supply, it undergoes an epithelial–mesenchymal transition, which increases cancer cell motility and invasiveness. The migratory and invasive cancer cells often exert aggressive cancer development or even cancer metastasis. In this study, we investigated a novel compound, 3-acetyl-5,8-dichloro-2-((2,4-dichlorophenyl)amino)quinolin-4(1H)-one (ADQ), that showed significant suppression of wound healing and cellular invasion. This compound also inhibited anchorage-independent cell growth, multicellular tumor spheroid survival/invasion, and metalloprotease activities. The anti-proliferative effects of ADQ were mediated by inhibition of the Akt pathway. In addition, ADQ reduced the expression of mesenchymal markers of cancer cells, which was associated with the suppressed expression of Twist1. In conclusion, ADQ successfully suppressed carcinogenic activity by inhibiting the Akt signaling pathway and Twist1, which suggests that ADQ may be an efficient candidate for cancer drug development.

scholarly journals Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 558
Author(s):  
Jin Kyung Seok ◽  
Eun-Hee Hong ◽  
Gabsik Yang ◽  
Hye Eun Lee ◽  
Sin-Eun Kim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Oxidized Phospholipids ◽  
Mcf7 Cells ◽  
Mesenchymal Transition ◽  
Tumor Tissues

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

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