Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Big Bang Tumor Growth and Clonal Evolution.

ABSTRACT: The advent and application of next-generation sequencing (NGS) technologies to tumor genomes has reinvigorated efforts to understand clonal evolution. Although tumor progression has traditionally been viewed as a gradual stepwise process, recent studies suggest that evolutionary rates in tumors can be variable with periods of punctuated mutational bursts and relative stasis. For example, Big Bang dynamics have been reported, wherein after transformation, growth occurs in the absence of stringent selection, consistent with effectively neutral evolution. Although first noted in colorectal tumors, effective neutrality may be relatively common. Additionally, punctuated evolution resulting from mutational bursts and cataclysmic genomic alterations have been described. In this review, we contrast these findings with the conventional gradualist view of clonal evolution and describe potential clinical and therapeutic implications of different evolutionary modes and tempos.

SUBMITTER: Sun R

PROVIDER: S-EPMC5932575 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Big Bang Tumor Growth and Clonal Evolution.

Sun Ruping R Hu Zheng Z Curtis Christina C

Cold Spring Harbor perspectives in medicine 20180501 5

The advent and application of next-generation sequencing (NGS) technologies to tumor genomes has reinvigorated efforts to understand clonal evolution. Although tumor progression has traditionally been viewed as a gradual stepwise process, recent studies suggest that evolutionary rates in tumors can be variable with periods of punctuated mutational bursts and relative stasis. For example, Big Bang dynamics have been reported, wherein after transformation, growth occurs in the absence of stringent ...[more]

PMID: 28710260

Similar Datasets

A Big Bang model of human colorectal tumor growth.

Project description:What happens in early, still undetectable human malignancies is unknown because direct observations are impractical. Here we present and validate a 'Big Bang' model, whereby tumors grow predominantly as a single expansion producing numerous intermixed subclones that are not subject to stringent selection and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors showed an absence of selective sweeps, uniformly high intratumoral heterogeneity (ITH) and subclone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear 'born to be bad', with subclone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH, with important clinical implications.

| S-EPMC4575589 | biostudies-literature

Drosophila Big bang regulates the apical cytocortex and wing growth through junctional tension.

Project description:Growth of epithelial tissues is regulated by a plethora of components, including signaling and scaffolding proteins, but also by junctional tension, mediated by the actomyosin cytoskeleton. However, how these players are spatially organized and functionally coordinated is not well understood. Here, we identify the Drosophila melanogaster scaffolding protein Big bang as a novel regulator of growth in epithelial cells of the wing disc by ensuring proper junctional tension. Loss of big bang results in the reduction of the regulatory light chain of nonmuscle myosin, Spaghetti squash. This is associated with an increased apical cell surface, decreased junctional tension, and smaller wings. Strikingly, these phenotypic traits of big bang mutant discs can be rescued by expressing constitutively active Spaghetti squash. Big bang colocalizes with Spaghetti squash in the apical cytocortex and is found in the same protein complex. These results suggest that in epithelial cells of developing wings, the scaffolding protein Big bang controls apical cytocortex organization, which is important for regulating cell shape and tissue growth.

| S-EPMC5839783 | biostudies-other

big bang gene modulates gut immune tolerance in Drosophila.

Project description:Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora. Here we describe the role of the big bang (bbg) gene, encoding multiple membrane-associated PDZ (PSD-95, Discs-large, ZO-1) domain-containing protein isoforms, in the modulation of the gut immune response. We show that in the adult Drosophila midgut, BBG is present at the level of the septate junctions, on the apical side of the enterocytes. In the absence of BBG, these junctions become loose, enabling the intestinal flora to trigger a constitutive activation of the anterior midgut immune response. This chronic epithelial inflammation leads to a reduced lifespan of bbg mutant flies. Clearing the commensal flora by antibiotics prevents the abnormal activation of the gut immune response and restores a normal lifespan. We now provide genetic evidence that Drosophila septate junctions are part of the gut immune barrier, a function that is evolutionarily conserved in mammals. Collectively, our data suggest that septate junctions are required to maintain the subtle balance between immune tolerance and immune response in the Drosophila gut, which represents a powerful model to study inflammatory bowel diseases.

| S-EPMC3581892 | biostudies-other

Digital psychiatry and COVID-19: the Big Bang effect for the NHS?

Project description:The COVID-19 pandemic has brought untold tragedies. However, one outcome has been the dramatically rapid replacement of face-to-face consultations and other meetings, including clinical multidisciplinary team meetings, with telephone calls or videoconferencing. By and large this form of remote consultation has received a warm welcome from both patients and clinicians. To date, human, technological and institutional barriers may have held back the integration of such approaches in routine clinical practice, particularly in the UK. As we move into the post-pandemic phase, it is vital that academic, educational and clinical leadership builds on this positive legacy of the COVID crisis. Telepsychiatry may be but one component of 'digital psychiatry' but its seismic evolution in the pandemic offers a possible opportunity to embrace and develop 'digital psychiatry' as a whole.

| S-EPMC7844168 | biostudies-literature

The apical scaffold big bang binds to spectrins and regulates the growth of Drosophila melanogaster wing discs.

Project description:During development, cell numbers are tightly regulated, ensuring that tissues and organs reach their correct size and shape. Recent evidence has highlighted the intricate connections between the cytoskeleton and the regulation of the key growth control Hippo pathway. Looking for apical scaffolds regulating tissue growth, we describe that Drosophila melanogaster big bang (Bbg), a poorly characterized multi-PDZ scaffold, controls epithelial tissue growth without affecting epithelial polarity and architecture. bbg-mutant tissues are smaller, with fewer cells that are less apically constricted than normal. We show that Bbg binds to and colocalizes tightly with the β-heavy-Spectrin/Kst subunit at the apical cortex and promotes Yki activity, F-actin enrichment, and the phosphorylation of the myosin II regulatory light chain Spaghetti squash. We propose a model in which the spectrin cytoskeleton recruits Bbg to the cortex, where Bbg promotes actomyosin contractility to regulate epithelial tissue growth.

| S-EPMC5839784 | biostudies-other

Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution.

Project description:The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities-a notion that we term "temporal collateral sensitivity." Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph(+) acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1-targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small-molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities.

| S-EPMC5152932 | biostudies-literature

Inflation of wood resources in European forests: The footprints of a big-bang.

Project description:The current increase in European forest resources forms a singularity across the globe. Whether this trend will persist, and how biological and economic trends feature it form crucial issues to green economy challenges and C sequestration. The present screening of Forest Europe 2015 statistics explored the features, inertia and limits of this expansion, and its relationships with countries' development, forest management and trade, intense in this area of the world. Persisting footprint of past demographic pressure on forests was identified, with opposed traces on their area and growing stock density. Steady growing stock (GS) increases, proportional to GS, not density-limited, and sustained by forest area increases, supported the view of an inflationary forest dynamic. Economic development and liberalism fostered both forest exploitation and production, yielding no significant impact on GS changes. Wood exports exerted a tension on forest exploitation and GS changes, thus lowering GS inflation but providing a resource security margin in the face of expected climate threats. Conflicting a common view, GS inflation and moderate felling-to-increment ratios make increased use of wood resources and C sequestration reconcilable, and GS expansion timely for ongoing EU forest policy processes. Anticipated adverse impacts of ongoing climate change were not clearly identified in these statistics.

| S-EPMC8612577 | biostudies-literature

Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution

Project description:In this study, using a murine model of Ph+ acute lymphoblastic leukemia (Ph+ ALL), a combined pharmacological profile and drug selection experimental approach identified distinct stages of tumor clonal evolution with vulnerabilities to sets of small molecules. Through genotypic, phenotypic, signaling, and binding measurements, we identified the mutation V299L in the ABL1 kinase domain as mediator for an on-target ABL1 inhibition and hence the sensitization phenotype. To further rule out any off-target effects, we performed RNA-seq analysis of select derived cell lines. Variant calls suggest that although there were other mutations, the only mutation shared among cell lines with the sensitization phenotype and that went from 0% to 100% variant allele frequency was c.895G>C, leading to BCR-ABL1 V299L. In addition, transcriptional profile does not suggest functional changes in BCR-ABL1 V299L and WT cell lines. RNA-seq of parental murine Ph+ acute lymphoblastic leukemia (Ph+ ALL) cell line and derived cell lines (via dose escalating concentrations of dasatinib or DMSO vehicle control).

2016-04-05 | E-GEOD-72910 | biostudies-arrayexpress

Selection-driven tumor evolution with public goods leads to patterns of clonal expansion consistent with neutral growth.

Project description:Cancers are the result of eco-evolutionary processes fueled by heritable phenotypic diversification and driven by environmentally dependent selection. Space represents a key growth-limiting ecological resource, the ability to explore this resource is likely under strong selection. Using agent-based modeling, we explored the interplay between phenotypic strategies centered on gaining access to new space through cell-extrinsic degradation of extracellular matrix barriers and the exploitation of this resource through maximizing cell proliferation. While cell proliferation is a cell-intrinsic property, newly accessed space represents a public good, which can benefit both producers and non-producers. We found that this interplay results in ecological succession, enabling emergence of large, heterogeneous, and highly proliferative populations. Even though in our simulations both remodeling and proliferation strategies were under strong positive selection, their interplay led to sub-clonal architecture that could be interpreted as evidence for neutral evolution, warranting cautious interpretation of inferences from sequencing of cancer genomes.

| S-EPMC7753957 | biostudies-literature

Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications.

Project description:The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution.

| S-EPMC4972528 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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