Predicting anti-cancer drug combination responses with a temporal cell state network model DOI Creative Commons
Deepraj Sarmah, Wesley O. Meredith,

Ian K. Weber

et al.

PLoS Computational Biology, Journal Year: 2023, Volume and Issue: 19(5), P. e1011082 - e1011082

Published: May 1, 2023

Cancer chemotherapy combines multiple drugs, but predicting the effects of drug combinations on cancer cell proliferation remains challenging, even for simple in vitro systems. We hypothesized that by combining knowledge single dose responses and state transition network dynamics, we could predict how a population cells will respond to combinations. tested this hypothesis here using three targeted inhibitors different cycle states two lines vitro. formulated Markov model capture temporal transitions between phases, with data constraining doses affect rates. This was able landscape all pairwise across ranges both no additional data. While further application lines, more networks, complex co-culture or vivo systems remain, work demonstrates currently available attainable information be sufficient prediction combination response

Language: Английский

The harsh microenvironment in early breast cancer selects for a Warburg phenotype DOI Creative Commons
Mehdi Damaghi, Jeffrey West, Mark Robertson‐Tessi

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(3)

Published: Jan. 15, 2021

Significance Glucose is converted to energy through “fermentation” or “oxidation.” Generally, if oxygen available, cells will oxidize glucose CO 2 because it more efficient than fermentation, which produces lactic acid. But Warburg noted that cancers ferment at a “remarkable” rate even O available! This “Warburg Effect” still misunderstood doesn’t make sense cell would when could get much by oxidizing it. The current paper goes the heart of this problem defining microenvironmental conditions exist in early select for Effect. important such are aggressive and like lead lethal.

Language: Английский

Citations

108
The Effects of COVID-19 on the Placenta During Pregnancy DOI Creative Commons

Habib Sadeghi Rad,

Joan Röhl, Nataly Stylianou

et al.

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Sept. 15, 2021

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a global pandemic. The virus primarily affects lungs where it induces distress ranging from mild to acute, however, there is growing body of evidence supporting its negative effects on other system organs that also carry ACE2 receptor, such as placenta. majority newborns delivered SARS-CoV-2 positive mothers test following delivery, suggesting are protective mechanisms within There appears be higher incidence pregnancy-related complications in mothers, miscarriage, restricted fetal growth, or still-birth. In this review, we discuss pathobiology COVID-19 maternal infection and potential adverse associated with viral infection, possibility transplacental transmission.

Language: Английский

Citations

86
Mathematical modelling reveals cellular dynamics within tumour spheroids DOI Creative Commons
Joshua A. Bull,

Franziska Mech,

Tom Quaiser

et al.

PLoS Computational Biology, Journal Year: 2020, Volume and Issue: 16(8), P. e1007961 - e1007961

Published: Aug. 18, 2020

Tumour spheroids are widely used as an in vitro assay for characterising the dynamics and response to treatment of different cancer cell lines. Their popularity is largely due reproducible manner which grow: diffusion nutrients oxygen from surrounding culture medium, their consumption by tumour cells, causes proliferation be localised at spheroid boundary. As grows, cells centre may become hypoxic die, forming a necrotic core. The pressure created localisation death generates cellular flow rim towards its Experiments Dorie et al. showed that this inert microspheres infiltrate into via advection surface, adding microbeads surface observing distribution over time. We use off-lattice hybrid agent-based model re-assess these experiments establish extent spatio-temporal data generated can infer kinetic parameters associated with they infiltrate. Variation parameters, such rate or sensitivity hypoxia, produce similar bulk growth but differing internal compositions (the proportion proliferating, hypoxic/quiescent necrotic/nutrient-deficient). show types experiment conducted could composition lines hypoxia average proliferation, note observations cannot within previous continuum models microbead infiltration rely on resolving trajectories individual microbeads.

Language: Английский

Citations

85
Normal tissue architecture determines the evolutionary course of cancer DOI Creative Commons
Jeffrey West, Ryan O. Schenck, Chandler Gatenbee

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: April 6, 2021

Abstract Cancer growth can be described as a caricature of the renewal process tissue origin, where architecture has strong influence on evolutionary dynamics within tumor. Using classic, well-studied model tumor evolution (a passenger-driver mutation model) we systematically alter spatial constraints and cell mixing rates to show how structure influences functional (driver) mutations genetic heterogeneity over time. This approach explores key mechanism behind both inter-patient intratumoral heterogeneity: competition for space. Time-varying leads an emergent transition from Darwinian premalignant subsequent invasive neutral growth. Initial determine mode (Darwinian neutral) without change in cell-specific rate or fitness effects. Driver acquisition during precancerous stage may modulated en route by combination two factors: limited cellular mixing. These factors occur naturally ductal carcinomas, branching topology network dictates rates.

Language: Английский

Citations

72
Spontaneous cell fusions as a mechanism of parasexual recombination in tumour cell populations DOI
Daria Miroshnychenko, Etienne Baratchart, Meghan C. Ferrall‐Fairbanks

et al.

Nature Ecology & Evolution, Journal Year: 2021, Volume and Issue: 5(3), P. 379 - 391

Published: Jan. 18, 2021

Language: Английский

Citations

65
Spatial structure impacts adaptive therapy by shaping intra-tumoral competition DOI Creative Commons
Maximilian Strobl, Jill Gallaher, Jeffrey West

et al.

Communications Medicine, Journal Year: 2022, Volume and Issue: 2(1)

Published: April 25, 2022

Adaptive therapy aims to tackle cancer drug resistance by leveraging resource competition between drug-sensitive and resistant cells. Here, we present a theoretical study of intra-tumoral during adaptive therapy, investigate under which circumstances it will be superior aggressive treatment.We develop analyse simple, 2-D, on-lattice, agent-based tumour model in cells are classified as fully or resistant. Subsequently, compare this its corresponding non-spatial ordinary differential equation model, fit longitudinal prostate-specific antigen data from 65 prostate patients undergoing intermittent androgen deprivation following biochemical recurrence.Leveraging the individual-based nature our explicitly demonstrate competitive suppression examine how different factors, such initial fraction costs, alter competition. This not only corroborates understanding but also reveals that with each other may play more important role solid tumours than was previously thought. To conclude, two case studies, implications work for: (i) mathematical modelling (ii) dynamics treatment, precursor therapy.Our shows tumour's spatial architecture is an factor provides insights into leverages both inter- intra-specific control resistance.

Language: Английский

Citations

46
Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues DOI Creative Commons
Calum Gabbutt, Ryan O. Schenck, Daniel J. Weisenberger

et al.

Nature Biotechnology, Journal Year: 2022, Volume and Issue: 40(5), P. 720 - 730

Published: Jan. 3, 2022

Abstract Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of renewal in adult tissues. Here, we show fluctuating DNA methylation marks can be used as cells where ongoing and demethylation cause repeated ‘flip–flops’ between methylated unmethylated states. We identify endogenous CpG (fCpG) sites using standard arrays develop a mathematical model quantitatively human stem from these data. Small intestinal crypts were inferred contain slightly more than colon, with slower replacement small intestine. Germline APC mutation increased number replacements per crypt. In blood, measured rapid expansion acute leukemia growth chronic disease. Thus, patterns somatic birth death are measurable (FMCs).

Language: Английский

Citations

43
Agent-based methods facilitate integrative science in cancer DOI Creative Commons
Jeffrey West, Mark Robertson‐Tessi, Alexander R.A. Anderson

et al.

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 33(4), P. 300 - 311

Published: Nov. 17, 2022

Language: Английский

Citations

43
Materials Design Innovations in Optimizing Cellular Behavior on Melt Electrowritten (MEW) Scaffolds DOI Creative Commons
Brenna L. Devlin, Mark C. Allenby, Jiongyu Ren

et al.

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: 34(18)

Published: Jan. 21, 2024

Abstract The field of melt electrowriting (MEW) has seen significant progress, bringing innovative advancements to the fabrication biomaterial scaffolds, and creating new possibilities for applications in tissue engineering beyond. Multidisciplinary collaboration across materials science, computational modeling, AI, bioprinting, microfluidics, dynamic culture systems offers promising opportunities gain deeper insights into complex biological systems. As focus shifts towards personalized medicine reduced reliance on animal models, multidisciplinary approach becomes indispensable. This review provides a concise overview current strategies innovations controlling optimizing cellular responses MEW highlighting potential scaffold material, architecture, modeling tools accelerate development efficient biomimetic Innovations material science incorporation biologics scaffolds have shown great adding complexity engineered These techniques pave way exciting regeneration, drug screening, cell therapies.

Language: Английский

Citations

12
Mathematical modeling of radiotherapy and its impact on tumor interactions with the immune system DOI Creative Commons
Rebecca Anne Bekker,

Sungjune Kim,

Shari Pilon‐Thomas

et al.

Neoplasia, Journal Year: 2022, Volume and Issue: 28, P. 100796 - 100796

Published: April 19, 2022

Radiotherapy is a primary therapeutic modality widely utilized with curative intent. Traditionally tumor response was hypothesized to be due high levels of cell death induced by irreparable DNA damage. However, the immunomodulatory aspect radiation now accepted. As such, interest into combination radiotherapy and immunotherapy increasing, synergy which has potential improve regression beyond that observed after either treatment alone. questions regarding timing (sequential vs concurrent) dose fractionation (hyper-, standard-, or hypo-fractionation) result in improved anti-tumor immune responses, thus potentially enhanced inhibition, remain. Here we discuss biological its properties before giving an overview pre-clinical data clinical trials concerned answering these questions. Finally, review published mathematical models impact on tumor-immune interactions. Ranging from considering microenvironment induction choice site setting metastatic disease, all have underlying feature common: push towards personalized therapy.

Language: Английский

Citations

38