Browsing by Author "Mani, Sendurai A."

Now showing 1 - 7 of 7
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    Coupling the modules of EMT and stemness: A tunable ‘stemness window’ model
    (Impact Journals, LLC., 2015) Jolly, Mohit Kumar; Jia, Dongya; Boareto, Marcelo; Mani, Sendurai A.; Pienta, Kenneth J.; Ben-Jacob, Eshel; Levine, Herbert; Center for Theoretical Biological Physics
    Metastasis of carcinoma involves migration of tumor cells to distant organs and initiate secondary tumors. Migration requires a complete or partial Epithelial-to-Mesenchymal Transition (EMT), and tumor-initiation requires cells possessing stemness. Epithelial cells (E) undergoing a complete EMT to become mesenchymal (M) have been suggested to be more likely to possess stemness. However, recent studies suggest that stemness can also be associated with cells undergoing a partial EMT (hybrid E/M phenotype). Therefore, the correlation between EMT and stemness remains elusive. Here, using a theoretical framework that couples the core EMT and stemness modules (miR-200/ZEB and LIN28/let-7), we demonstrate that the positioning of 'stemness window' on the 'EMT axis' need not be universal; rather it can be fine-tuned. Particularly, we present OVOL as an example of a modulating factor that, due to its coupling with miR-200/ZEB/LIN28/let-7 circuit, fine-tunes the EMT-stemness interplay. Coupling OVOL can inhibit the stemness likelihood of M and elevate that of the hybrid E/M (partial EMT) phenotype, thereby pulling the 'stemness window' away from the M end of 'EMT axis'. Our results unify various apparently contradictory experimental findings regarding the interconnection between EMT and stemness, corroborate the emerging notion that partial EMT associates with stemness, and offer new testable predictions.
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    Distinguishing mechanisms underlying EMT tristability
    (Springer International Publishing, 2017) Jia, Dongya; Jolly, Mohit K.; Tripathi, Satyendra C.; Den Hollander, Petra; Huang, Bin; Lu, Mingyang; Celiktas, Muge; Ramirez-Peña, Esmeralda; Ben-Jacob, Eshel; Onuchic, José Nelson; Hanash, Samir M.; Mani, Sendurai A.; Levine, Herbert
    Abstract Background The Epithelial-Mesenchymal Transition (EMT) endows epithelial-looking cells with enhanced migratory ability during embryonic development and tissue repair. EMT can also be co-opted by cancer cells to acquire metastatic potential and drug-resistance. Recent research has argued that epithelial (E) cells can undergo either a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype that typically displays collective migration, or a complete EMT to adopt a mesenchymal (M) phenotype that shows individual migration. The core EMT regulatory network - miR-34/SNAIL/miR-200/ZEB1 - has been identified by various studies, but how this network regulates the transitions among the E, E/M, and M phenotypes remains controversial. Two major mathematical models – ternary chimera switch (TCS) and cascading bistable switches (CBS) - that both focus on the miR-34/SNAIL/miR-200/ZEB1 network, have been proposed to elucidate the EMT dynamics, but a detailed analysis of how well either or both of these two models can capture recent experimental observations about EMT dynamics remains to be done. Results Here, via an integrated experimental and theoretical approach, we first show that both these two models can be used to understand the two-step transition of EMT - E→E/M→M, the different responses of SNAIL and ZEB1 to exogenous TGF-β and the irreversibility of complete EMT. Next, we present new experimental results that tend to discriminate between these two models. We show that ZEB1 is present at intermediate levels in the hybrid E/M H1975 cells, and that in HMLE cells, overexpression of SNAIL is not sufficient to initiate EMT in the absence of ZEB1 and FOXC2. Conclusions These experimental results argue in favor of the TCS model proposing that miR-200/ZEB1 behaves as a three-way decision-making switch enabling transitions among the E, hybrid E/M and M phenotypes.
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    Fluorinated Graphene Oxide: a New Multimodal Material for Biological Applications
    (Wiley, 2013) Romero-Aburto, Rebeca; Narayanan, Tharangattu N.; Nagaoka, Yutaka; Hasumura, Takashi; Mitcham, Trevor M.; Fukuda, Takahiro; Cox, Paris J.; Bouchard, Richard R.; Maekawa, Toru; Kumar, Sakthi; Torti, Suzy V.; Mani, Sendurai A.; Ajayan, Pulickel M.
    Fluorinated graphene oxide (FGO) is reported for the first time as a magnetically responsive drug carrier that can serve as a MRI and photoacoustic contrast agent, under pre-clinical settings, as well as a photothermal therapy Its hydrophilic nature facilitates biocompatibility. FGO as a broad wavelength absorber, with high charge transfer and strong nonlinear scattering is optimal for NIR laser-induced hyperthermia.
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    Hybrid 2D Nanomaterials as Dual-mode Contrast Agents in Cellular Imaging
    (Wiley-VCH Verlag, 2012) Narayanan, Tharangattu N.; Gupta, Bipin K.; Vithayathil, Sajna A.; Aburto, Rebeca R.; Mani, Sendurai A.; Taha-Tijerina, Jaime; Xie, Bin; Kaipparettu, Benny A.; Torti, Suzy V.; Ajayan, Pulickel M.
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    Metal-Free Dual Modal Contrast Agents Based on Fluorographene Quantum Dots
    (Wiley, 2016) Radhakrishnan, Sruthi; Samanta, Atanu; Sudeep, Parambath M.; Maldonado, Kiersten L.; Mani, Sendurai A.; Acharya, Ghanashyam; Tiwary, Chandra Sekhar; Singh, Abhishek K.; Ajayan, Pulickel M.
    Fluorographene quantum dots prepared from fluorinated graphene oxide (FGO) show a linear dependence of the magnetization on the applied field. This is further supported by DFT calculations taking into account a few possible systems of functionalized graphene quantum dots. The inherent magnetism, high concentration of fluorine and cyto-compatibility of these quantum dots promise potential application as a dual modal agent for proton and 19F based Magnetic Resonance Imaging which is investigated here. A metal free dual modal contrast agent would bring about a great change in the efficiency and resolution of this widely used imaging tool.
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    Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype
    (Royal Society Publishing, 2016) Boareto, Marcelo; Jolly, Mohit Kumar; Goldman, Aaron; Pietilä, Mika; Mani, Sendurai A.; Sengupta, Shiladitya; Ben-Jacob, Eshel; Levine, Herbert; Onuchic, José Nelson; Center for Theoretical Biological Physics
    Metastasis can involve repeated cycles of epithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition. Cells can also undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype that allows the migration of adhering cells to form a cluster of circulating tumour cells. These clusters can be apoptosis-resistant and possess an increased metastatic propensity as compared to the cells that undergo a complete EMT (mesenchymal cells). Hence, identifying the key players that can regulate the formation and maintenance of such clusters may inform anti-metastasis strategies. Here, we devise a mechanism-based theoretical model that links cell–cell communication via Notch-Delta-Jagged signalling with the regulation of EMT. We demonstrate that while both Notch-Delta and Notch-Jagged signalling can induce EMT in a population of cells, only Jagged-dominated Notch signalling, but not Delta-dominated signalling, can lead to the formation of clusters containing hybrid E/M cells. Our results offer possible mechanistic insights into the role of Jagged in tumour progression, and offer a framework to investigate the effects of other microenvironmental signals during metastasis.
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    Stability of the hybrid epithelial/mesenchymal phenotype
    (Impact Journals, LLC, 2016) Jolly, Mohit Kumar; Tripathi, Satyendra C.; Jia, Dongya; Mooney, Steven M.; Celiktas, Muge; Hanash, Samir M.; Mani, Sendurai A.; Pienta, Kenneth J.; Ben-Jacob, Eshel; Levine, Herbert; Center for Theoretical Biological Physics; Systems, Synthetic, and Physical Biology Program
    Epithelial-to-Mesenchymal Transition (EMT) and its reverse - Mesenchymal to Epithelial Transition (MET) - are hallmarks of cellular plasticity during embryonic development and cancer metastasis. During EMT, epithelial cells lose cell-cell adhesion and gain migratory and invasive traits either partially or completely, leading to a hybrid epithelial/mesenchymal (hybrid E/M) or a mesenchymal phenotype respectively. Mesenchymal cells move individually, but hybrid E/M cells migrate collectively as observed during gastrulation, wound healing, and the formation of tumor clusters detected as Circulating Tumor Cells (CTCs). Typically, the hybrid E/M phenotype has largely been tacitly assumed to be transient and 'metastable'. Here, we identify certain 'phenotypic stability factors' (PSFs) such as GRHL2 that couple to the core EMT decision-making circuit (miR-200/ZEB) and stabilize hybrid E/M phenotype. Further, we show that H1975 lung cancer cells can display a stable hybrid E/M phenotype and migrate collectively, a behavior that is impaired by knockdown of GRHL2 and another previously identified PSF - OVOL. In addition, our computational model predicts that GRHL2 can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of these PSFs may be predictive of poor patient outcome. Finally, based on these specific examples, we deduce certain network motifs that can stabilize the hybrid E/M phenotype. Our results suggest that partial EMT, i.e. a hybrid E/M phenotype, need not be 'metastable', and strengthen the emerging notion that partial EMT, but not necessarily a complete EMT, is associated with aggressive tumor progression.