Deciphering the Dynamics of Epithelial-Mesenchymal Transition and Cancer Stem Cells in Tumor Progression

Bocci, Federico; Levine, Herbert; Onuchic, José N.; Jolly, Mohit Kumar

doi:10.1007/s40778-019-0150-3

Cited by 32 publications

(30 citation statements)

References 97 publications

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“…These results offer a unifying framework for the concepts of intratumoral heterogeneity, EMT, and CSCs and indicate the crucial role of JAG1 in simultaneously promoting a hybrid E/M phenotype and the acquisition of stem properties. In this framework, stemness is envisioned as a feature that can be reversibly gained or lost by cancer cells, as opposed to a more classical model where stemness can be only lost via cell differentiation (55,56). Importantly, Notch signaling need not to be the only factor that dictates the spatial segregation of different CSC subsets, and the "hunt" for a complete set of variables that characterize the EMT and CSC status remains open.…”

Section: Inflammatory Cytokines Increase the Csc Population By Enhancingmentioning

confidence: 99%

Toward understanding cancer stem cell heterogeneity in the tumor microenvironment

Bocci

Gearhart-Serna

Boareto

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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263

241

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The epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) formation are two paramount processes driving tumor progression, therapy resistance, and cancer metastasis. Recent experiments show that cells with varying EMT and CSC phenotypes are spatially segregated in the primary tumor. The underlying mechanisms generating such spatiotemporal dynamics in the tumor microenvironment, however, remain largely unexplored. Here, we show through a mechanism-based dynamical model that the diffusion of EMT-inducing signals such as TGF-β, together with noncell autonomous control of EMT and CSC decision making via the Notch signaling pathway, can explain experimentally observed disparate localization of subsets of CSCs with varying EMT phenotypes in the tumor. Our simulations show that the more mesenchymal CSCs lie at the invasive edge, while the hybrid epithelial/mesenchymal (E/M) CSCs reside in the tumor interior. Further, motivated by the role of Notch-Jagged signaling in mediating EMT and stemness, we investigated the microenvironmental factors that promote Notch-Jagged signaling. We show that many inflammatory cytokines such as IL-6 that can promote Notch-Jagged signaling can (i) stabilize a hybrid E/M phenotype, (ii) increase the likelihood of spatial proximity of hybrid E/M cells, and (iii) expand the fraction of CSCs. To validate the predicted connection between Notch-Jagged signaling and stemness, we knocked down JAG1 in hybrid E/M SUM149 human breast cancer cells in vitro. JAG1 knockdown significantly restricted tumor organoid formation, confirming the key role that Notch-Jagged signaling can play in tumor progression. Together, our integrated computational–experimental framework reveals the underlying principles of spatiotemporal dynamics of EMT and CSCs.

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Section: Inflammatory Cytokines Increase the Csc Population By Enhancingmentioning

confidence: 99%

Toward understanding cancer stem cell heterogeneity in the tumor microenvironment

Bocci

Gearhart-Serna

Boareto

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

263

241

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“…This is manifested in the model as an intermediate fraction of E-cadherin expressing states. Such states were recently suggested to characterize mobile cell clusters that may play an important role in metastasis [12].…”

Section: Resultsmentioning

confidence: 99%

“…These models generally include a combination of transcriptional and post-transcriptional regulatory elements [11]. Small motif models have been developed which describe the two-state landscape [12][13][14][15]. Some models are tristable, by construction giving rise to stable E/M states and a hybrid state.…”

Section: Introductionmentioning

confidence: 99%

Local and global features of genetic networks supporting a phenotypic switch

2020

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Phenotypic switches are associated with alterations in the cell's gene expression profile and are vital to many aspects of biology. Previous studies have identified local motifs of the genetic regulatory network that could underlie such switches. Recent advancements allowed the study of networks at the global, many-gene, level; however, the relationship between the local and global scales in giving rise to phenotypic switches remains elusive. In this work, we studied the epithelial-mesenchymal transition (EMT) using a gene regulatory network model. This model supports two clusters of stable steady-states identified with the epithelial and mesenchymal phenotypes, and a range of intermediate less stable hybrid states, whose importance in cancer has been recently highlighted. Using an array of network perturbations and quantifying the resulting landscape, we investigated how features of the network at different levels give rise to these landscape properties. We found that local connectivity patterns affect the landscape in a mostly incremental manner; in particular, a specific previously identified double-negative feedback motif is not required when embedded in the full network, because the landscape is maintained at a global level. Nevertheless, despite the distributed nature of the switch, it is possible to find combinations of a few local changes that disrupt it. At the level of network architecture, we identified a crucial role for peripheral genes that act as incoming signals to the network in creating clusters of states. Such incoming signals are a signature of modularity and are expected to appear also in other biological networks. Hybrid states between epithelial and mesenchymal arise in the model due to barriers in the interaction between genes, causing hysteresis at all connections. Our results suggest emergent switches can neither be pinpointed to local motifs, nor do they arise as typical properties of random network ensembles. Rather, they arise through an interplay between the nature of local interactions, and the core-periphery structure induced by the modularity of the cell.

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“…The existence of one or more hybrid epithelial/mesenchymal states capable to invade while maintaining cell-cell adhesion has been proposed as a possible explanation for the different modes of invasion (43). Supporting this hypothesis, hybrid epithelial/mesenchymal phenotype(s) have been associated with stemness and tumor-initiation ability (31,(44)(45)(46)(47), while inducing a complete EMT has been shown to even restrict tumor aggressiveness and metastatic potential in some cases (48)(49)(50)(51). Here, we show that a model of only partial EMT that can be associated with a partially conserved epithelial program can still give rise to different regimes characterized by more individual or more collective cell migration.…”

Section: Is a Complete Emt Necessary For Cancer Metastases?mentioning

confidence: 95%

A biophysical model of Epithelial-Mesenchymal Transition uncovers the frequency and size distribution of Circulating Tumor Cell clusters across cancer types

Bocci

2019

Preprint

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The gain of cellular motility via the epithelial-mesenchymal transition (EMT) is considered crucial in the metastatic cascade. Cells undergoing EMT to varying extents are launched into the bloodstream as single circulating tumor cells (CTCs) or multi-cellular clusters. The frequency and size distributions of these multicellular clusters has been recently measured, but the underlying mechanisms enabling these different modes of migration remain poorly understood. We present a biophysical model that couples the epithelialmesenchymal phenotypic transition and cell migration to explain these different modes of cancer cell migration. With this reduced physical model, we identify a transition from individual migration to clustered cell migration that is regulated by the rate of EMT and the degree of cooperativity between cells during migration. This single cell to clustered migration transition can robustly recapitulate cluster size distributions observed experimentally across several cancer types, thus suggesting the existence of common features in the mechanisms of cell migration during metastasis. Furthermore, we identify three main mechanisms that can facilitate the formation and dissemination of large clusters: first, mechanisms that prevent a complete EMT and instead increase the population of hybrid Epithelial/Mesenchymal (E/M) cells; second, multiple intermediate E/M states that give rise to heterogeneous clusters formed by cells with different epithelial-mesenchymal traits; and third, non-cell-autonomous induction of EMT via cell-tocell signaling that gives rise to spatial correlations among cells in a tissue. Overall, this biophysical model represents a first step toward bridging the gap between the molecular and biophysical understanding of EMT and various modes of cancer cell migration, and highlights that a complete EMT might not be required for metastasis. Statement of significanceThe Epithelial-Mesenchymal Transition (EMT) confers motility and invasive traits to cancer cells. These cells can then enter the circulatory system both as single cells or as multi-cellular clusters to initiate metastases.We develop a biophysical model to investigate how EMT at the single cell level can give rise to a solitary or clustered cell migration. This model quantitatively reproduces cluster size distributions reported in human circulation and mouse models, therefore suggesting similar mechanisms in cancer cell migration across different cancer types. Moreover, we show that a partial EMT to a hybrid epithelial/mesenchymal cell state is sufficient to explain both single cell and clustered migration, therefore questioning the necessity of a complete EMT for cancer metastasis.

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Deciphering the Dynamics of Epithelial-Mesenchymal Transition and Cancer Stem Cells in Tumor Progression

Cited by 32 publications

References 97 publications

Toward understanding cancer stem cell heterogeneity in the tumor microenvironment

Toward understanding cancer stem cell heterogeneity in the tumor microenvironment

Local and global features of genetic networks supporting a phenotypic switch

A biophysical model of Epithelial-Mesenchymal Transition uncovers the frequency and size distribution of Circulating Tumor Cell clusters across cancer types

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