Browsing by Author "Jolly, Mohit Kumar"
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Item Analysis of Hierarchical Organization in Gene Expression Networks Reveals Underlying Principles of Collective Tumor Cell Dissemination and Metastatic Aggressiveness of Inflammatory Breast Cancer(Frontiers, 2018) Tripathi, Shubham; Jolly, Mohit Kumar; Woodward, Wendy A.; Levine, Herbert; Deem, Michael W.; Bioengineering; Physics and AstronomyClusters of circulating tumor cells (CTCs), despite being rare, may account for more than 90% of metastases. Cells in these clusters do not undergo a complete epithelial-to-mesenchymal transition (EMT), but retain some epithelial traits as compared to individually disseminating tumor cells. Determinants of single cell dissemination versus collective dissemination remain elusive. Inflammatory breast cancer (IBC), a highly aggressive breast cancer subtype that chiefly metastasizes via CTC clusters, is a promising model for studying mechanisms of collective tumor cell dissemination. Previous studies, motivated by a theory that suggests physical systems with hierarchical organization tend to be more adaptable, have found that the expression of metastasis-associated genes is more hierarchically organized in cases of successful metastases. Here, we used the cophenetic correlation coefficient (CCC) to quantify the hierarchical organization in the expression of two distinct gene sets, collective dissemination-associated genes and IBC-associated genes, in cancer cell lines and in tumor samples from breast cancer patients. Hypothesizing that a higher CCC for collective dissemination-associated genes and for IBC-associated genes would be associated with retention of epithelial traits enabling collective dissemination and with worse disease progression in breast cancer patients, we evaluated the correlation of CCC with different phenotypic groups. The CCC of both the abovementioned gene sets, the collective dissemination-associated genes and the IBC-associated genes, was higher in (a) epithelial cell lines as compared to mesenchymal cell lines and (b) tumor samples from IBC patients as compared to samples from non-IBC breast cancer patients. A higher CCC of both gene sets was also correlated with a higher rate of metastatic relapse in breast cancer patients. In contrast, neither the levels of CDH1 gene expression nor gene set enrichment analysis (GSEA) of the abovementioned gene sets could provide similar insights. These results suggest that retention of some epithelial traits in disseminating tumor cells as IBC progresses promotes successful breast cancer metastasis. The CCC provides additional information regarding the organizational complexity of gene expression in comparison to GSEA. We have shown that the CCC may be a useful metric for investigating the collective dissemination phenotype and a prognostic factor for IBC.Item Computational Modeling of the Crosstalk Between Macrophage Polarization and Tumor Cell Plasticity in the Tumor Microenvironment(Frontiers, 2019) Li, Xuefei; Jolly, Mohit Kumar; George, Jason T.; Pienta, Kenneth J.; Levine, Herbert; Bioengineering; Physics and AstronomyTumor microenvironments contain multiple cell types interacting among one another via different signaling pathways. Furthermore, both cancer cells and different immune cells can display phenotypic plasticity in response to these communicating signals, thereby leading to complex spatiotemporal patterns that can impact therapeutic response. Here, we investigate the crosstalk between cancer cells and macrophages in a tumor microenvironment through in silico (computational) co-culture models. In particular, we investigate how macrophages of different polarization (M1 vs. M2) can interact with epithelial-mesenchymal plasticity of cancer cells, and conversely, how cancer cells exhibiting different phenotypes (epithelial vs. mesenchymal) can influence the polarization of macrophages. Based on interactions documented in the literature, an interaction network of cancer cells and macrophages is constructed. The steady states of the network are then analyzed. Various interactions were removed or added into the constructed-network to test the functions of those interactions. Also, parameters in the mathematical models were varied to explore their effects on the steady states of the network. In general, the interactions between cancer cells and macrophages can give rise to multiple stable steady-states for a given set of parameters and each steady state is stable against perturbations. Importantly, we show that the system can often reach one type of stable steady states where cancer cells go extinct. Our results may help inform efficient therapeutic strategies.Item 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; Bioengineering; Biosciences; Physics and Astronomy; Center for Theoretical Biological PhysicsMetastasis 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.Item EMT and MET: necessary or permissive for metastasis?(Wiley, 2017) Jolly, Mohit Kumar; Ware, Kathryn E.; Gilja, Shivee; Somarelli, Jason A.; Levine, Herbert; Bioengineering; Center for Theoretical Biological PhysicsEpithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition (MET) have been suggested to play crucial roles in metastatic dissemination of carcinomas. These phenotypic transitions between states are not binary. Instead, carcinoma cells often exhibit a spectrum of epithelial/mesenchymal phenotype(s). While epithelial/mesenchymal plasticity has been observed preclinically and clinically, whether any of these phenotypic transitions are indispensable for metastatic outgrowth remains an unanswered question. Here, we focus on epithelial/mesenchymal plasticity in metastatic dissemination and propose alternative mechanisms for successful dissemination and metastases beyond the traditional EMT/MET view. We highlight multiple hypotheses that can help reconcile conflicting observations, and outline the next set of key questions that can offer valuable insights into mechanisms of metastasis in multiple tumor models.Item Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?(Wiley, 2017) Jolly, Mohit Kumar; Tripathi, Satyendra C.; Somarelli, Jason A.; Hanash, Samir M.; Levine, Herbert; Bioengineering; Center for Theoretical Biological PhysicsPhenotypic plasticity, the ability of cells to reversibly alter their phenotypes in response to signals, presents a significant clinical challenge to treating solid tumors. Tumor cells utilize phenotypic plasticity to evade therapies, metastasize, and colonize distant organs. As a result, phenotypic plasticity can accelerate tumor progression. A well-studied example of phenotypic plasticity is the bidirectional conversions among epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M) phenotype(s). These conversions can alter a repertoire of cellular traits associated with multiple hallmarks of cancer, such as metabolism, immune evasion, invasion, and metastasis. To tackle the complexity and heterogeneity of these transitions, mathematical models have been developed that seek to capture the experimentally verified molecular mechanisms and act as ‘hypothesis-generating machines’. Here, we discuss how these quantitative mathematical models have helped us explain existing experimental data, guided further experiments, and provided an improved conceptual framework for understanding how multiple intracellular and extracellular signals can drive E/M plasticity at both the single-cell and population levels. We also discuss the implications of this plasticity in driving multiple aggressive facets of tumor progression.Item Gene expression profiles of inflammatory breast cancer reveal high heterogeneity across the epithelial-hybrid-mesenchymal spectrum(Elsevier, 2021) Chakraborty, Priyanka; George, Jason T; Woodward, Wendy A; Levine, Herbert; Jolly, Mohit Kumar; Center for Theoretical Biological PhysicsInflammatory breast cancer (IBC) is a highly aggressive breast cancer that metastasizes largely via tumor emboli, and has a 5-year survival rate of less than 30%. No unique genomic signature has yet been identified for IBC nor has any specific molecular therapeutic been developed to manage the disease. Thus, identifying gene expression signatures specific to IBC remains crucial. Here, we compare various gene lists that have been proposed as molecular footprints of IBC using different clinical samples as training and validation sets and using independent training algorithms, and determine their accuracy in identifying IBC samples in three independent datasets. We show that these gene lists have little to no mutual overlap, and have limited predictive accuracy in identifying IBC samples. Despite this inconsistency, single-sample gene set enrichment analysis (ssGSEA) of IBC samples correlate with their position on the epithelial-hybrid-mesenchymal spectrum. This positioning, together with ssGSEA scores, improves the accuracy of IBC identification across the three independent datasets. Finally, we observed that IBC samples robustly displayed a higher coefficient of variation in terms of EMT scores, as compared to non-IBC samples. Pending verification that this patient-to-patient variability extends to intratumor heterogeneity within a single patient, these results suggest that higher heterogeneity along the epithelial-hybrid-mesenchymal spectrum can be regarded to be a hallmark of IBC and a possibly useful biomarker.Item The hybrid epithelial/mesenchymal phenotype and its implications in cancer metastasis(2016-11-17) Jolly, Mohit Kumar; Levine, HerbertMore than 90% of cancer-related deaths occur because cancer cells metastasize, i.e. invade the surrounding tissue, travel throughout the body, and form tumors at distant organs. Metastasis is often fueled by Epithelial-to-Mesenchymal Transition (EMT) that enables cells to migrate and invade, and its reverse Mesenchymal-to-Epithelial Transition (MET) that facilitates cells to shed migration and regain adhesion to colonize other organs. While undergoing EMT or MET, cells can adopt a hybrid epithelial/mesenchymal (E/M) phenotype through which they can both adhere and migrate, leading to collective migration as clusters of Circulating Tumor Cells (CTCs) that can be apoptosis-resistant and can initiate 50 times more tumors as compared to individually migrating CTCs. However, the hybrid E/M remains poorly characterized and has been tacitly assumed to be ‘metastable’ or transient. This study, through integrating mathematical modeling with wet-lab experiments, suggests that the hybrid E/M phenotype can be quite stable and its stability can aggravate tumor progression. First, we model the core regulatory network underlying EMT/MET – interconnected feedback loops among miR-34, miR-200, ZEB, SNAIL families – to predict that it can act as a ‘three-way’ switch enabling three phenotypes – epithelial (high miR-200, low ZEB), mesenchymal (low miR-200, high ZEB) and hybrid E/M (medium miR-200, medium ZEB). Second, GRHL2 and OVOL1/2 are predicted to stabilize a hybrid E/M phenotype and then confirmed experimentally in H1975 lung cancer cells that display a stable hybrid E/M phenotype. Third, modeling the interconnections of core EMT network with that regulating tumor-initiation potential (LIN28/let-7) predicts that a hybrid E/M, but not necessarily a fully mesenchymal, phenotype associates with higher tumor-initiation potential. Finally, integrating the core EMT network with intercellular Notch signaling, we predict that Notch-Jagged signaling can give rise to clusters of cells in a hybrid E/M phenotype. This prediction corroborates with our experimental observations that the drug-resistant tumor-initiating cells display elevated levels of Notch-Jagged signaling, reflecting the metastatic potential of hybrid E/M cells that can form clusters of CTCs. These results strongly argue that cancer cells in a hybrid E/M phenotype can be the key ‘bad actors’ of metastasis and identify novel targets – OVOL1/2, GRHL2 and JAG1 – to curb metastatic load.Item Implications of the hybrid epithelial/mesenchymal phenotype in metastasis(Frontiers Media S.A., 2015) Jolly, Mohit Kumar; Boareto, Marcelo; Huang, Bin; Jia, Dongya; Lu, Mingyang; Ben-Jacob, Eshel; Onuchic, José Nelson; Levine, Herbert; Bioengineering; Chemistry; Biosciences; Center for Theoretical Biological Physics; Systems, Synthetic, and Physical BiologyTransitions between epithelial and mesenchymal phenotypes - the epithelial to -mesenchymal transition (EMT) and its reverse the mesenchymal to epithelial transition (MET) - are hallmarks of cancer metastasis. While transitioning between the epithelial and mesenchymal phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) (i.e., partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g., adhesion) and mesenchymal (e.g., migration) properties, thereby allowing them to move collectively as clusters. If these clusters reach the bloodstream intact, they can give rise to clusters of circulating tumor cells (CTCs), as have often been seen experimentally. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a "three-way" switch giving rise to three distinct phenotypes - E, M and hybrid E/M - and present a theoretical framework that can elucidate the role of many other players in regulating epithelial plasticity. Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell-cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs. These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype. Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies. Finally, we discuss the multiple advantages that the partial EMT or hybrid E/M phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary "bad actors" of metastasis.Item Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer(AIP Publishing LLC, 2018) Jolly, Mohit Kumar; Preca, Bogdan-Tiberius; Tripathi, Satyendra C.; Jia, Dongya; George, Jason T.; Hanash, Samir M.; Brabletz, Thomas; Stemmler, Marc P.; Maurer, Jochen; Levine, Herbert; Bioengineering; Center for Theoretical Biological PhysicsAberrant activation of epithelial-mesenchymal transition (EMT) in carcinoma cells contributes to increased migration and invasion, metastasis, drug resistance, and tumor-initiating capacity. EMT is not always a binary process; rather, cells may exhibit a hybrid epithelial/mesenchymal (E/M) phenotype. ZEB1—a key transcription factor driving EMT—can both induce and maintain a mesenchymal phenotype. Recent studies have identified two novel autocrine feedback loops utilizing epithelial splicing regulatory protein 1 (ESRP1), hyaluronic acid synthase 2 (HAS2), and CD44 which maintain high levels of ZEB1. However, how the crosstalk between these feedback loops alters the dynamics of epithelial-hybrid-mesenchymal transition remains elusive. Here, using an integrated theoretical-experimental framework, we identify that these feedback loops can enable cells to stably maintain a hybrid E/M phenotype. Moreover, computational analysis identifies the regulation of ESRP1 as a crucial node, a prediction that is validated by experiments showing that knockdown of ESRP1 in stable hybrid E/M H1975 cells drives EMT. Finally, in multiple breast cancer datasets, high levels of ESRP1, ESRP1/HAS2, and ESRP1/ZEB1 correlate with poor prognosis, supporting the relevance of ZEB1/ESRP1 and ZEB1/HAS2 axes in tumor progression. Together, our results unravel how these interconnected feedback loops act in concert to regulate ZEB1 levels and to drive the dynamics of epithelial-hybrid-mesenchymal transition.Item A mechanism-based computational model to capture the interconnections among epithelial-mesenchymal transition, cancer stem cells and Notch-Jagged signaling(Oncotarget, 2018) Bocci, Federico; Jolly, Mohit Kumar; George, Jason Thomas; Levine, Herbert; Onuchic, José Nelson; Bioengineering; Biosciences; Chemistry; Physics and Astronomy; Center for Theoretical Biological PhysicsEpithelial-mesenchymal transition (EMT) and cancer stem cell (CSCs) formation are two fundamental and well-studied processes contributing to cancer metastasis and tumor relapse. Cells can undergo a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype or a complete EMT to attain a mesenchymal one. Similarly, cells can reversibly gain or lose 'stemness'. This plasticity in cell states is modulated by signaling pathways such as Notch. However, the interconnections among the cell states enabled by EMT, CSCs and Notch signaling remain elusive. Here, we devise a computational model to investigate the coupling among the core decision-making circuits for EMT, CSCs and Notch. Our model predicts that hybrid E/M cells are most likely to associate with stem-like traits and enhanced Notch-Jagged signaling – a pathway implicated in therapeutic resistance. Further, we show that the position of the 'stemness window' on the 'EMT axis' is varied by altering the coupling strength between EMT and CSC circuits, and/or modulating Notch signaling. Finally, we analyze the gene expression profile of CSCs from several cancer types and observe a heterogeneous distribution along the 'EMT axis', suggesting that different subsets of CSCs may exist with varying phenotypes along the epithelial-mesenchymal axis. We further investigate therapeutic perturbations such as treatment with metformin, a drug associated with decreased cancer incidence and increased lifespan of patients. Our mechanism-based model explains how metformin can both inhibit EMT and blunt the aggressive potential of CSCs simultaneously, by driving the cells out of a hybrid E/M stem-like state with enhanced Notch-Jagged signaling.Item Modeling the Transitions between Collective and Solitary Migration Phenotypes in Cancer Metastasis(Macmillan Publishers Limited, 2015) Huang, Bin; Jolly, Mohit Kumar; Lu, Mingyang; Tsarfaty, Ilan; Ben-Jacob, Eshel; Onuchic, José Nelson; Bioengineering; Biosciences; Chemistry; Physics and Astronomy; Center for Theoretical Biological PhysicsCellular plasticity during cancer metastasis is a major clinical challenge. Two key cellular plasticity mechanisms —Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Amoeboid Transition (MAT) – have been carefully investigated individually, yet a comprehensive understanding of their interconnections remains elusive. Previously, we have modeled the dynamics of the core regulatory circuits for both EMT (miR-200/ZEB/miR-34/SNAIL) and MAT (Rac1/RhoA). We now extend our previous work to study the coupling between these two core circuits by considering the two microRNAs (miR-200 and miR-34) as external signals to the core MAT circuit. We show that this coupled circuit enables four different stable steady states (phenotypes) that correspond to hybrid epithelial/mesenchymal (E/M), mesenchymal (M), amoeboid (A) and hybrid amoeboid/mesenchymal (A/M) phenotypes. Our model recapitulates the metastasis-suppressing role of the microRNAs even in the presence of EMT-inducing signals like Hepatocyte Growth Factor (HGF). It also enables mapping the microRNA levels to the transitions among various cell migration phenotypes. Finally, it offers a mechanistic understanding for the observed phenotypic transitions among different cell migration phenotypes, specifically the Collective-to-Amoeboid Transition (CAT).Item 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; Bioengineering; Biosciences; Chemistry; Physics and Astronomy; Center for Theoretical Biological PhysicsMetastasis 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.Item NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype(Oxford University Press, 2019) Bocci, Federico; Tripathi, Satyendra C.; Vilchez Mercedes, Samuel A.; George, Jason Thomas; Casabar, Julian P.; Wong, Pak Kin; Hanash, Samir M.; Levine, Herbert; Onuchic, José Nelson; Jolly, Mohit KumarThe 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’.Item Nrf2 Modulates the Hybrid Epithelial/Mesenchymal Phenotype and Notch Signaling During Collective Cancer Migration(Frontiers Media S.A., 2022) Vilchez Mercedes, Samuel A.; Bocci, Federico; Ahmed, Mona; Eder, Ian; Zhu, Ninghao; Levine, Herbert; Onuchic, José N.; Jolly, Mohit Kumar; Wong, Pak Kin; Center for Theoretical Biological PhysicsHybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. It remains a challenge to understand how these cell states, which are mostly non-existent in healthy tissue, become stable phenotypes participating in 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 combination of immunocytochemistry, single cell biosensors, and computational modeling, 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 also demonstrate that Nrf2 and EMT signaling are spatially coordinated near the leading edge. In particular, computational analysis of an Nrf2-EMT-Notch network and experimental modulation of Nrf2 by pharmacological treatment or CRISPR/Cas9 gene editing reveal that Nrf2 stabilizes a hybrid E/M phenotype which is 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 at the leading edge, which correlates with the formation of leader cells and protruding tips. Altogether, our results provide direct evidence that Nrf2 acts as a phenotypic stability factor in restricting complete EMT and plays an important role in coordinating collective cancer migration.Item NRF2-dependent Epigenetic Regulation can Promote the Hybrid Epithelial/Mesenchymal Phenotype(Frontiers Media S.A., 2022) Jia, Wen; Jolly, Mohit Kumar; Levine, HerbertThe 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.Item Operating principles of Notch–Delta–Jagged module of cell–cell communication(IOP Publishing, 2015) Jolly, Mohit Kumar; Boareto, Marcelo; Lu, Mingyang; Onuchic, José Nelson; Clementi, Cecilia; Ben-Jacob, Eshel; Bioengineering; Biosciences; Chemistry; Physics and Astronomy; Center for Theoretical Biological PhysicsNotch pathway is an evolutionarily conserved cell–cell communication mechanism governing cell-fate during development and tumor progression. It is activated when Notch receptor of one cell binds to either of its ligand—Delta or Jagged—of another cell. Notch–Delta (ND) signaling forms a two-way switch, and two cells interacting via ND signaling adopt different fates—Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Notch–Delta–Jagged signaling (NDJ) behaves as a three-way switch and enables an additional fate—hybrid Sender/Receiver (S/R) (medium ligand, medium receptor). Here, by extending our framework of NDJ signaling for a two-cell system, we show that higher production rate of Jagged, but not that of Delta, expands the range of parameters for which both cells attain the hybrid S/R state. Conversely, glycosyltransferase Fringe and cis-inhibition reduces this range of conditions, and reduces the relative stability of the hybrid S/R state, thereby promoting cell-fate divergence and consequently lateral inhibition-based patterns. Lastly, soluble Jagged drives the cells to attain the hybrid S/R state, and soluble Delta drives them to be Receivers. We also discuss the critical role of hybrid S/R state in promoting cancer metastasis by enabling collective cell migration and expanding cancer stem cell (CSC) population.Item OVOL guides the epithelial-hybrid-mesenchymal transition(Impact Journals, LLC, 2015) Jia, Dongya; Jolly, Mohit Kumar; Boareto, Marcelo; Parsana, Princy; Mooney, Steven M.; Pienta, Kenneth J.; Levine, Herbert; Ben-Jacob, Eshel; Bioengineering; Biosciences; Physics and Astronomy; Center for Theoretical Biological PhysicsMetastasis involves multiple cycles of Epithelial-to-Mesenchymal Transition (EMT) and its reverse-MET. Cells can also undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype that has maximum cellular plasticity and allows migration of Circulating Tumor Cells (CTCs) as a cluster. Hence, deciphering the molecular players helping to maintain the hybrid E/M phenotype may inform anti-metastasis strategies. Here, we devised a mechanism-based mathematical model to couple the transcription factor OVOL with the core EMT regulatory network miR-200/ZEB that acts as a three-way switch between the E, E/M and M phenotypes. We show that OVOL can modulate cellular plasticity in multiple ways - restricting EMT, driving MET, expanding the existence of the hybrid E/M phenotype and turning both EMT and MET into two-step processes. Our theoretical framework explains the differences between the observed effects of OVOL in breast and prostate cancer, and provides a platform for investigating additional signals during metastasis.asis.Item Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory(MDPI, 2017) Jia, Dongya; Jolly, Mohit Kumar; Kulkarni, Prakash; Levine, Herbert; BioengineeringWaddington’s epigenetic landscape, a famous metaphor in developmental biology, depicts how a stem cell progresses from an undifferentiated phenotype to a differentiated one. The concept of “landscape” in the context of dynamical systems theory represents a high-dimensional space, in which each cell phenotype is considered as an “attractor” that is determined by interactions between multiple molecular players, and is buffered against environmental fluctuations. In addition, biological noise is thought to play an important role during these cell-fate decisions and in fact controls transitions between different phenotypes. Here, we discuss the phenotypic transitions in cancer from a dynamical systems perspective and invoke the concept of “cancer attractors”—hidden stable states of the underlying regulatory network that are not occupied by normal cells. Phenotypic transitions in cancer occur at varying levels depending on the context. Using epithelial-to-mesenchymal transition (EMT), cancer stem-like properties, metabolic reprogramming and the emergence of therapy resistance as examples, we illustrate how phenotypic plasticity in cancer cells enables them to acquire hybrid phenotypes (such as hybrid epithelial/mesenchymal and hybrid metabolic phenotypes) that tend to be more aggressive and notoriously resilient to therapies such as chemotherapy and androgen-deprivation therapy. Furthermore, we highlight multiple factors that may give rise to phenotypic plasticity in cancer cells, such as (a) multi-stability or oscillatory behaviors governed by underlying regulatory networks involved in cell-fate decisions in cancer cells, and (b) network rewiring due to conformational dynamics of intrinsically disordered proteins (IDPs) that are highly enriched in cancer cells. We conclude by discussing why a therapeutic approach that promotes “recanalization”, i.e., the exit from “cancer attractors” and re-entry into “normal attractors”, is more likely to succeed rather than a conventional approach that targets individual molecules/pathways.Item Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins(Wolters Kluwer, 2016) Mooney, Steven M.; Jolly, Mohit Kumar; Levine, Herbert; Kulkarni, Prakash; Bioengineering; Physics and Astronomy; Center for Theoretical Biological PhysicsA striking characteristic of cancer cells is their remarkable phenotypic plasticity, which is the ability to switch states or phenotypes in response to environmental fluctuations. Phenotypic changes such as a partial or complete epithelial to mesenchymal transition (EMT) that play important roles in their survival and proliferation, and development of resistance to therapeutic treatments, are widely believed to arise due to somatic mutations in the genome. However, there is a growing concern that such a deterministic view is not entirely consistent with multiple lines of evidence, which indicate that stochasticity may also play an important role in driving phenotypic plasticity. Here, we discuss how stochasticity in protein interaction networks (PINs) may play a key role in determining phenotypic plasticity in prostate cancer (PCa). Specifically, we point out that the key players driving transitions among different phenotypes (epithelial, mesenchymal, and hybrid epithelial/mesenchymal), including ZEB1, SNAI1, OVOL1, and OVOL2, are intrinsically disordered proteins (IDPs) and discuss how plasticity at the molecular level may contribute to stochasticity in phenotypic switching by rewiring PINs. We conclude by suggesting that targeting IDPs implicated in EMT in PCa may be a new strategy to gain additional insights and develop novel treatments for this disease, which is the most common form of cancer in adult men.Item Phenotypic Plasticity, Bet-Hedging, and Androgen Independence in Prostate Cancer: Role of Non-Genetic Heterogeneity(Frontiers, 2018) Jolly, Mohit Kumar; Kulkarni, Prakash; Weninger, Keith; Orban, John; Levine, Herbert; Bioengineering; Physics and AstronomyIt is well known that genetic mutations can drive drug resistance and lead to tumor relapse. Here, we focus on alternate mechanisms-those without mutations, such as phenotypic plasticity and stochastic cell-to-cell variability that can also evade drug attacks by giving rise to drug-tolerant persisters. The phenomenon of persistence has been well-studied in bacteria and has also recently garnered attention in cancer. We draw a parallel between bacterial persistence and resistance against androgen deprivation therapy in prostate cancer (PCa), the primary standard care for metastatic disease. We illustrate how phenotypic plasticity and consequent mutation-independent or non-genetic heterogeneity possibly driven by protein conformational dynamics can stochastically give rise to androgen independence in PCa, and suggest that dynamic phenotypic plasticity should be considered in devising therapeutic dosing strategies designed to treat and manage PCa.