Modeling Cell-to-Cell Communication Networks Using Response-Time Distributions.

Cell-to-cell communication networks have critical roles in coordinating diverse organismal processes, such as tissue development or immune cell response. However, compared with intracellular signal transduction networks, the function and engineering principles of cell-to-cell communication networks are far less understood. Major complications include: cells are themselves regulated by complex intracellular signaling networks; individual cells are heterogeneous; and output of any one cell can recursively become an additional input signal to other cells. Here, we make use of a framework that treats intracellular signal transduction networks as "black boxes" with characterized input-to-output response relationships. We study simple cell-to-cell communication circuit motifs and find conditions that generate bimodal responses in time, as well as mechanisms for independently controlling synchronization and delay of cell-population responses. We apply our modeling approach to explain otherwise puzzling data on cytokine secretion onset times in T cells. Our approach can be used to predict communication network structure using experimentally accessible input-to-output measurements and without detailed knowledge of intermediate steps

Cellular Heterogeneity: Do Differences Make a Difference?

A central challenge of biology is to understand how individual cells process information and respond to perturbations. Much of our knowledge is based on ensemble measurements. However, cell-to-cell differences are always present to some degree in any cell population, and the ensemble behaviors of a population may not represent the behaviors of any individual cell. Here, we discuss examples of when heterogeneity cannot be ignored and describe practical strategies for analyzing and interpreting cellular heterogeneity

Only Two Ways to Achieve Perfection

The functional repertoire of a network is determined by its topology. Ma et al. (2009) analyze enzyme networks with three nodes and take a reverse-engineering approach to ask how many core network topologies can establish perfect adaptation, the ability to reset after perturbation. Surprisingly, the answer is just two

A multi-modal data resource for investigating topographic heterogeneity in patient-derived xenograft tumors.

Patient-derived xenografts (PDXs) are an essential pre-clinical resource for investigating tumor biology. However, cellular heterogeneity within and across PDX tumors can strongly impact the interpretation of PDX studies. Here, we generated a multi-modal, large-scale dataset to investigate PDX heterogeneity in metastatic colorectal cancer (CRC) across tumor models, spatial scales and genomic, transcriptomic, proteomic and imaging assay modalities. To showcase this dataset, we present analysis to assess sources of PDX variation, including anatomical orientation within the implanted tumor, mouse contribution, and differences between replicate PDX tumors. A unique aspect of our dataset is deep characterization of intra-tumor heterogeneity via immunofluorescence imaging, which enables investigation of variation across multiple spatial scales, from subcellular to whole tumor levels. Our study provides a benchmark data resource to investigate PDX models of metastatic CRC and serves as a template for future, quantitative investigations of spatial heterogeneity within and across PDX tumor models

The Developmental Rules of Neural Superposition in Drosophila

SummaryComplicated neuronal circuits can be genetically encoded, but the underlying developmental algorithms remain largely unknown. Here, we describe a developmental algorithm for the specification of synaptic partner cells through axonal sorting in the Drosophila visual map. Our approach combines intravital imaging of growth cone dynamics in developing brains of intact pupae and data-driven computational modeling. These analyses suggest that three simple rules are sufficient to generate the seemingly complex neural superposition wiring of the fly visual map without an elaborate molecular matchmaking code. Our computational model explains robust and precise wiring in a crowded brain region despite extensive growth cone overlaps and provides a framework for matching molecular mechanisms with the rules they execute. Finally, ordered geometric axon terminal arrangements that are not required for neural superposition are a side product of the developmental algorithm, thus elucidating neural circuit connectivity that remained unexplained based on adult structure and function alone.PaperCli

An Actin-Based Wave Generator Organizes Cell Motility

Although many of the regulators of actin assembly are known, we do not understand how these components act together to organize cell shape and movement. To address this question, we analyzed the spatial dynamics of a key actin regulator—the Scar/WAVE complex—which plays an important role in regulating cell shape in both metazoans and plants. We have recently discovered that the Hem-1/Nap1 component of the Scar/WAVE complex localizes to propagating waves that appear to organize the leading edge of a motile immune cell, the human neutrophil. Actin is both an output and input to the Scar/WAVE complex: the complex stimulates actin assembly, and actin polymer is also required to remove the complex from the membrane. These reciprocal interactions appear to generate propagated waves of actin nucleation that exhibit many of the properties of morphogenesis in motile cells, such as the ability of cells to flow around barriers and the intricate spatial organization of protrusion at the leading edge. We propose that cell motility results from the collective behavior of multiple self-organizing waves

Patterns of basal signaling heterogeneity can distinguish cellular populations with different drug sensitivities

Non small cell lung cancer H460 clones exhibit a high degree of heterogeneity in signaling states.Clones with similar patterns of basal signaling heterogeneity have similar paclitaxel sensitivities.Models of signaling heterogeneity among the clones can be used to classify sensitivity to paclitaxel for other cancer populations

Systems-level analyses identify extensive coupling among gene expression machines

Here, we develop computational methods to assess and consolidate large, diverse protein interaction data sets, with the objective of identifying proteins involved in the coupling of multicomponent complexes within the yeast gene expression pathway. From among ∼43 000 total interactions and 2100 proteins, our methods identify known structural complexes, such as the spliceosome and SAGA, and functional modules, such as the DEAD-box helicases, within the interaction network of proteins involved in gene expression. Our process identifies and ranks instances of three distinct, biologically motivated motifs, or patterns of coupling among distinct machineries involved in different subprocesses of gene expression. Our results confirm known coupling among transcription, RNA processing, and export, and predict further coupling with translation and nonsense-mediated decay. We systematically corroborate our analysis with two independent, comprehensive experimental data sets. The methods presented here may be generalized to other biological processes and organisms to generate principled, systems-level network models that provide experimentally testable hypotheses for coupling among biological machines

A Density-Dependent Switch Drives Stochastic Clustering and Polarization of Signaling Molecules

Positive feedback plays a key role in the ability of signaling molecules to form highly localized clusters in the membrane or cytosol of cells. Such clustering can occur in the absence of localizing mechanisms such as pre-existing spatial cues, diffusional barriers, or molecular cross-linking. What prevents positive feedback from amplifying inevitable biological noise when an un-clustered “off” state is desired? And, what limits the spread of clusters when an “on” state is desired? Here, we show that a minimal positive feedback circuit provides the general principle for both suppressing and amplifying noise: below a critical density of signaling molecules, clustering switches off; above this threshold, highly localized clusters are recurrently generated. Clustering occurs only in the stochastic regime, suggesting that finite sizes of molecular populations cannot be ignored in signal transduction networks. The emergence of a dominant cluster for finite numbers of molecules is partly a phenomenon of random sampling, analogous to the fixation or loss of neutral mutations in finite populations. We refer to our model as the “neutral drift polarity model.” Regulating the density of signaling molecules provides a simple mechanism for a positive feedback circuit to robustly switch between clustered and un-clustered states. The intrinsic ability of positive feedback both to create and suppress clustering is a general mechanism that could operate within diverse biological networks to create dynamic spatial organization