165 research outputs found
Prostate-Associated Gene 4 (PAGE4): Leveraging the Conformational Dynamics of a Dancing Protein Cloud as a Therapeutic Target.
Prostate cancer (PCa) is a leading cause of mortality and morbidity globally. While genomic alterations have been identified in PCa, in contrast to some other cancers, use of such information to personalize treatment is still in its infancy. Here, we discuss how PAGE4, a protein which appears to act both as an oncogenic factor as well as a metastasis suppressor, is a novel therapeutic target for PCa. Inhibiting PAGE4 may be a viable strategy for low-risk PCa where it is highly upregulated. Conversely, PAGE4 expression is downregulated in metastatic PCa and, therefore, reinstituting its sustained expression may be a promising option to subvert or attenuate androgen-resistant PCa. Thus, fine-tuning the levels of PAGE4 may represent a novel approach for personalized medicine in PCa
Quantifying cancer epithelial-mesenchymal plasticity and its association with stemness and immune response
Cancer cells can acquire a spectrum of stable hybrid epithelial/mesenchymal
(E/M) states during epithelial-mesenchymal transition (EMT). Cells in these
hybrid E/M phenotypes often combine epithelial and mesenchymal features and
tend to migrate collectively commonly as small clusters. Such collectively
migrating cancer cells play a pivotal role in seeding metastases and their
presence in cancer patients indicates an adverse prognostic factor. Moreover,
cancer cells in hybrid E/M phenotypes tend to be more associated with stemness
which endows them with tumor-initiation ability and therapy resistance. Most
recently, cells undergoing EMT have been shown to promote immune suppression
for better survival. A systematic understanding of the emergence of hybrid E/M
phenotypes and the connection of EMT with stemness and immune suppression would
contribute to more effective therapeutic strategies. In this review, we first
discuss recent efforts combining theoretical and experimental approaches to
elucidate mechanisms underlying EMT multi-stability (i.e. the existence of
multiple stable phenotypes during EMT) and the properties of hybrid E/M
phenotypes. Following we discuss non-cell-autonomous regulation of EMT by cell
cooperation and extracellular matrix. Afterwards, we discuss various metrics
that can be used to quantify EMT spectrum. We further describe possible
mechanisms underlying the formation of clusters of circulating tumor cells.
Last but not least, we summarize recent systems biology analysis of the role of
EMT in the acquisition of stemness and immune suppression.Comment: 50 pages, 6 figure
Theoretical and computational tools to model multistable gene regulatory networks
The last decade has witnessed a surge of theoretical and computational models
to describe the dynamics of complex gene regulatory networks, and how these
interactions can give rise to multistable and heterogeneous cell populations.
As the use of theoretical modeling to describe genetic and biochemical circuits
becomes more widespread, theoreticians with mathematics and physics backgrounds
routinely apply concepts from statistical physics, non-linear dynamics, and
network theory to biological systems. This review aims at providing a clear
overview of the most important methodologies applied in the field while
highlighting current and future challenges, and includes hands-on tutorials to
solve and simulate some of the archetypical biological system models used in
the field. Furthermore, we provide concrete examples from the existing
literature for theoreticians that wish to explore this fast-developing field.
Whenever possible, we highlight the similarities and differences between
biochemical and regulatory networks and classical systems typically studied in
non-equilibrium statistical and quantum mechanics.Comment: 73 pages, 12 figure
EMT and MET: necessary or permissive for metastasis?
Epithelial-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
Analysis of hierarchical organization in gene expression networks reveals underlying principles of collective tumor cell dissemination and metastatic aggressiveness of inflammatory breast cancer
Clusters of circulating tumor cells (CTCs), although rare, may account for
more than 95% of metastases. Inflammatory breast cancer (IBC) is a highly
aggressive subtype that chiefly metastasizes via CTC clusters. Theory suggests
that physical systems with hierarchical organization tend to be more adaptable
due to their ability to efficiently span the set of available states. We used
the cophenetic correlation coefficient (CCC) to quantify the hierarchical
organization in the expression of collective dissemination associated and IBC
associated genes, and found that the CCC of both gene sets was higher in (a)
epithelial cell lines as compared to mesenchymal cell lines and (b) IBC tumor
samples as compared to non-IBC breast cancer samples. A higher CCC of both
networks was also correlated with a higher rate of metastatic relapse in breast
cancer patients. Gene set enrichment analysis could not provide similar
insights, indicating that the CCC provides additional information regarding the
organizational complexity of gene expression. These results suggest that
retention of epithelial traits in disseminating tumor cells as IBC progresses
promotes successful metastasis and the CCC may be a prognostic factor for IBC.Comment: 38 pages, 13 figure
Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?
Phenotypic 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
Link updating strategies influence consensus decisions as a function of the direction of communication
Consensus decision-making in social groups strongly depends on communication
links that determine to whom individuals send, and from whom they receive,
information. Here, we ask how consensus decisions are affected by strategic
updating of links and how this effect varies with the direction of
communication. We quantified the co-evolution of link and opinion dynamics in a
large population with binary opinions using mean-field numerical simulations of
two voter-like models of opinion dynamics: an Incoming model (where individuals
choose who to receive opinions from) and an Outgoing model (where individuals
choose who to send opinions to). We show that individuals can bias group-level
outcomes in their favor by breaking disagreeing links while receiving opinions
(Incoming Model) and retaining disagreeing links while sending opinions
(Outgoing Model). Importantly, these biases can help the population avoid
stalemates and achieve consensus. However, the role of disagreement avoidance
is diluted in the presence of strong preferences - highly stubborn individuals
can shape decisions to favor their preferences, giving rise to non-consensus
outcomes. We conclude that collectively changing communication structures can
bias consensus decisions, as a function of the strength of preferences and the
direction of communication
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Functional balance between Tcf21-Slug defines cellular plasticity and migratory modalities in high grade serous ovarian cancer cell lines.
Cellular plasticity and transitional phenotypes add to complexities of cancer metastasis that can be initiated by single cell epithelial to mesenchymal transition (EMT) or cooperative cell migration (CCM). Our study identifies novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma (HGSC). Differential expression and sub-cellular localization associate Tcf21, Slug with epithelial, mesenchymal phenotypes respectively; however gene manipulation approaches identify their association with additional intermediate phenotypic states, implying the existence of a multi-step epithelial-mesenchymal transition program. Live imaging further associated distinct migratory modalities with the Tcf21/Slug status of cell systems and discerned proliferative/passive CCM, active CCM and EMT modes of migration. Tcf21-Slug balance identified across a phenotypic spectrum in HGSC cell lines, associated with micro-environment induced transitions and the emergence of an epithelial phenotype following drug exposure. Phenotypic transitions and associated functionalities following drug exposure were affirmed to ensue from occupancy of Slug promoter E-box sequences by Tcf21. Our study effectively provides a framework for understanding the relevance of ovarian cancer plasticity as a function of two transcription factors
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