Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A Circuit for Secretion-coupled Cellular Autonomy in Multicellular Eukaryotic cells

ABSTRACT: Cancers represent complex autonomous systems, displaying self-sufficiency through its ability to 'secrete-and-sense' growth-factors: a poorly understood phenomenon. Using an integrated systems and experimental approach, here we dissect the impact of a feedback-coupled GTPase circuit within the secretory pathway that imparts secretion-coupled autonomy. The circuit is assembled when the Ras-superfamily monomeric-GTPase Arf1, and heterotrimeric-GTPase Giabg and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two negative feedback-loops within the circuit create closed-loop control (CLC), allow the two GTPases to coregulate each other, and convert the expected switch-like behavior of Arf1-dependent secretion into an unexpected dose response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self-sustained by stimulus-proportionate secretion. Proteomic studies and protein-protein interaction network analyses pinpoint growth factors (e.g., the epidermal growth factor) as key stimuli for such self-sustenance. Findings highlight how enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion-coupled autonomy of growth factors.

SUBMITTER: Lingxia Qiao

PROVIDER: S-SCDT-10_15252-MSB_202211127 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Computational implementation of a tunable multicellular memory circuit for engineered eukaryotic consortia.

Project description:Cells are complex machines capable of processing information by means of an entangled network of molecular interactions. A crucial component of these decision-making systems is the presence of memory and this is also a specially relevant target of engineered synthetic systems. A classic example of memory devices is a 1-bit memory element known as the flip-flop. Such system can be in principle designed using a single-cell implementation, but a direct mapping between standard circuit design and a living circuit can be cumbersome. Here we present a novel computational implementation of a 1-bit memory device using a reliable multicellular design able to behave as a set-reset flip-flop that could be implemented in yeast cells. The dynamics of the proposed synthetic circuit is investigated with a mathematical model using biologically-meaningful parameters. The circuit is shown to behave as a flip-flop in a wide range of parameter values. The repression strength for the NOT logics is shown to be crucial to obtain a good flip-flop signal. Our model also shows that the circuit can be externally tuned to achieve different memory states and dynamics, such as persistent and transient memory. We have characterized the parameter domains for robust memory storage and retrieval as well as the corresponding time response dynamics.

| S-EPMC4598587 | biostudies-literature

Multicellular bacteria deploy the type VI secretion system to preemptively strike neighboring cells.

Project description:The Type VI Secretion System (T6SS) functions in bacteria as a contractile nanomachine that punctures and delivers lethal effectors to a target cell. Virtually nothing is known about the lifestyle or physiology that dictates when bacteria normally produce their T6SS, which prevents a clear understanding of how bacteria benefit from its action in their natural habitat. Proteus mirabilis undergoes a characteristic developmental process to coordinate a multicellular swarming behavior and will discriminate itself from another Proteus isolate during swarming, resulting in a visible boundary termed a Dienes line. Using transposon mutagenesis, we discovered that this recognition phenomenon requires the lethal action of the T6SS. All mutants identified in the genetic screen had insertions within a single 33.5-kb region that encodes a T6SS and cognate Hcp-VrgG-linked effectors. The identified T6SS and primary effector operons were characterized by killing assays, by construction of additional mutants, by complementation, and by examining the activity of the type VI secretion system in real-time using live-cell microscopy on opposing swarms. We show that lethal T6SS-dependent activity occurs when a dominant strain infiltrates deeply beyond the boundary of the two swarms. Using this multicellular model, we found that social recognition in bacteria, underlying killing, and immunity to killing all require cell-cell contact, can be assigned to specific genes, and are dependent on the T6SS. The ability to survive a lethal T6SS attack equates to "recognition". In contrast to the current model of T6SS being an offensive or defensive weapon our findings support a preemptive mechanism by which an entire population indiscriminately uses the T6SS for contact-dependent delivery of effectors during its cooperative mode of growth.

| S-EPMC3764213 | biostudies-literature

Cellular memory in eukaryotic chemotaxis.

Project description:Natural chemical gradients to which cells respond chemotactically are often dynamic, with both spatial and temporal components. A primary example is the social amoeba Dictyostelium, which migrates to the source of traveling waves of chemoattractant as part of a self-organized aggregation process. Despite its physiological importance, little is known about how cells migrate directionally in response to traveling waves. The classic back-of-the-wave problem is how cells chemotax toward the wave source, even though the spatial gradient reverses direction in the back of the wave. Here, we address this problem by using microfluidics to expose cells to traveling waves of chemoattractant with varying periods. We find that cells exhibit memory and maintain directed motion toward the wave source in the back of the wave for the natural period of 6 min, but increasingly reverse direction for longer wave periods. Further insights into cellular memory are provided by experiments quantifying cell motion and localization of a directional-sensing marker after rapid gradient switches. The results can be explained by a model that couples adaptive directional sensing to bistable cellular memory. Our study shows how spatiotemporal cues can guide cell migration over large distances.

| S-EPMC4210025 | biostudies-literature

Single cell RNAseq coupled with TCR repertoire analysis of thymocytes in thymus autonomy and turnover

Project description:Wild type thymi were transplanted into wild recipients (turnover) or Rag2-/-gc-/- mice (autonomy) and, after 28 days of transplant, thymocytes (double negative 3 and 4, immature CD8 single positive and CD4 CD8 double positive) were sorted and single cell RNAseq and TCR repertoire analysis performed

2021-04-12 | GSE160135 | GEO

Engineering microscale cellular niches for three-dimensional multicellular co-cultures.

Project description:Modeling the in vivo microenvironment typically involves placing cells in a three-dimensional (3D) extracellular matrix (ECM) in physiologically relevant context with respect to other cells. The mechanical and chemical features of 3D microenvironments play important roles in tissue engineering, tumor growth and metastasis, and in defining stem cell niches, and it is increasingly recognized that cells behave much differently when surrounded by a 3D ECM than when anchored to a 2D substrate. To create microenvironments that more closely mimic in vivo settings, here we describe a novel microfluidic device that allows multiple discrete constructs of 3D cell-laden hydrogels to be patterned in a sequence of simple steps. The microfluidic platform allows for real-time imaging of the interactions between multiple cell types exposed to both autocrine and paracrine signaling molecules, all within a 3D ECM environment. Detailed modeling determined that surface tension, hydrophobic interactions, and spatial geometry were important factors in containing the gels within distinct separate channels during the filling process. This allowed us to pattern multiple gel types side-by-side and pattern 3D gels spatially with tight dimensional control. Cells embedded in gels could be patterned by culturing MDA-MB-231 metastatic breast cancer cells and RAW 264.1 macrophage cells within distinct collagen type I and Matrigel ECM environments, respectively. Over a 7 day culture experiment, RAW cells invaded into neighboring gels containing MDA-MB-231 cells, but not into gels lacking cells. These studies demonstrate the versatility and potential of this new microfluidic platform to engineer 3D microscale architectures to investigate cell-cell and cell-matrix interactions.

| S-EPMC3758562 | biostudies-literature

A distinct brain-β-cell circuit regulates insulin secretion

Project description:Hypothalamic neurons are multisynaptically connected to pancreatic islet β-cells.

2022-02-01 | GSE188856 | GEO

GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis.

Project description:Hematopoietic stem cells (HSCs) originate from hemogenic endothelium within the aorta-gonad-mesonephros (AGM) region of the mammalian embryo. The relationship between genetic circuits controlling stem cell genesis and multi-potency is not understood. A Gata2 cis element (+9.5) enhances Gata2 expression in the AGM and induces the endothelial to HSC transition. We demonstrated that GATA-2 rescued hematopoiesis in +9.5(-/-) AGMs. As G-protein-coupled receptors (GPCRs) are the most common targets for FDA-approved drugs, we analyzed the GPCR gene ensemble to identify GATA-2-regulated GPCRs. Of the 20 GATA-2-activated GPCR genes, four were GATA-1-activated, and only Gpr65 expression resembled Gata2. Contrasting with the paradigm in which GATA-2-activated genes promote hematopoietic stem and progenitor cell genesis/function, our mouse and zebrafish studies indicated that GPR65 suppressed hematopoiesis. GPR65 established repressive chromatin at the +9.5 site, restricted occupancy by the activator Scl/TAL1, and repressed Gata2 transcription. Thus, a Gata2 cis element creates a GATA-2-GPCR circuit that limits positive regulators that promote hematopoiesis.

| S-EPMC4788764 | biostudies-literature

Monitoring microbial metabolites using an inductively coupled resonance circuit.

Project description:We present a new approach to monitor microbial population dynamics in emulsion droplets via changes in metabolite composition, using an inductively coupled LC resonance circuit. The signal measured by such resonance detector provides information on the magnetic field interaction with the bacterial culture, which is complementary to the information accessible by other detection means, based on electric field interaction, i.e. capacitive or resistive, as well as optical techniques. Several charge-related factors, including pH and ammonia concentrations, were identified as possible contributors to the characteristic of resonance detector profile. The setup enables probing the ionic byproducts of microbial metabolic activity at later stages of cell growth, where conventional optical detection methods have no discriminating power.

| S-EPMC4533006 | biostudies-literature

Peroxicretion: a novel secretion pathway in the eukaryotic cell.

Project description:BACKGROUND: Enzyme production in microbial cells has been limited to secreted enzymes or intracellular enzymes followed by expensive down stream processing. Extracellular enzymes consists mainly of hydrolases while intracellular enzymes exhibit a much broader diversity. If these intracellular enzymes could be secreted by the cell the potential of industrial applications of enzymes would be enlarged. Therefore a novel secretion pathway for intracellular proteins was developed, using peroxisomes as secretion vesicles. RESULTS: Peroxisomes were decorated with a Golgi derived v-SNARE using a peroxisomal membrane protein as an anchor. This allowed the peroxisomes to fuse with the plasma membrane. Intracellular proteins were transported into the peroxisomes by adding a peroxisomal import signal (SKL tag). The proteins which were imported in the peroxisomes, were released into the extra-cellular space through this artificial secretion pathway which was designated peroxicretion. This concept was supported by electron microscopy studies. CONCLUSION: Our results demonstrate that it is possible to reroute the intracellular trafficking of vesicles by changing the localisation of SNARE molecules, this approach can be used in in vivo biological studies to clarify the different control mechanisms regulating intracellular membrane trafficking. In addition we demonstrate peroxicretion of a diverse set of intracellular proteins. Therefore, we anticipate that the concept of peroxicretion may revolutionize the production of intracellular proteins from fungi and other microbial cells, as well as from mammalian cells.

| S-EPMC2693430 | biostudies-literature

Secretion of parathyroid hormone may be coupled to insulin secretion in humans.

Project description:ObjectiveParathyroid hormone (PTH) is a key hormone in regulation of calcium homeostasis and its secretion is regulated by calcium. Secretion of PTH is attenuated during intake of nutrients, but the underlying mechanism(s) are unknown. We hypothesized that insulin acts as an acute regulator of PTH secretion.MethodsIntact PTH was measured in plasma from patients with T1D and matched healthy individuals during 4-h oral glucose tolerance tests (OGTT) and isoglycemic i.v. glucose infusions on 2 separate days. In addition, expression of insulin receptors on surgical specimens of parathyroid glands was assessed by immunochemistry (IHC) and quantitative PCR (qPCR).ResultsThe inhibition of PTH secretion was more pronounced in healthy individuals compared to patients with T1D during an OGTT (decrementalAUC0-240min: -5256 ± 3954 min × ng/L and -2408 ± 1435 min × ng/L, P = 0.030). Insulin levels correlated significantly and inversely with PTH levels, also after adjusting for levels of several gut hormones and BMI (P = 0.002). Expression of insulin receptors in human parathyroid glands was detected by both IHC and qPCR.ConclusionOur study suggests that insulin may act as an acute regulator of PTH secretion in humans.

| S-EPMC7424341 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data