Emergent dynamics of underlying regulatory network links EMT and androgen receptor-dependent resistance in prostate cancer DOI Creative Commons
Rashi Jindal, Abheepsa Nanda, Maalavika Pillai

и другие.

Computational and Structural Biotechnology Journal, Год журнала: 2023, Номер 21, С. 1498 - 1509

Опубликована: Янв. 1, 2023

Advanced prostate cancer patients initially respond to hormone therapy, be it in the form of androgen deprivation therapy or second-generation therapies, such as abiraterone acetate enzalutamide. However, most men with eventually develop resistance. This resistance can arise through multiple mechanisms, genetic mutations, epigenetic non-genetic pathways, lineage plasticity along epithelial-mesenchymal neuroendocrine-like axes. These mechanisms often co-exist within a single patient's tumor and overlap cell. There exists growing need better understand how phenotypic heterogeneity results from emergent dynamics regulatory networks governing independence. Here, we investigated network connecting drivers receptor (AR) splice variant-mediated independence those transition. Model simulations for this revealed four possible phenotypes: epithelial-sensitive (ES), epithelial-resistant (ER), mesenchymal-resistant (MR) mesenchymal-sensitive (MS), latter phenotype occurring rarely. We observed that well-coordinated "teams" regulators working antagonistically enable these phenotypes. model predictions are supported by transcriptomic datasets both at single-cell bulk levels, including vitro EMT induction models clinical samples. Further, our reveal spontaneous stochastic switching between ES MR states. Addition immune checkpoint molecule, PD-L1, was able capture interactions AR, mesenchymal marker SNAIL, which also confirmed quantitative experiments. systems-level understanding driver could aid transitions progression cancers help identifying novel therapeutic strategies targets.

Язык: Английский

EMT/MET plasticity in cancer and Go-or-Grow decisions in quiescence: the two sides of the same coin? DOI Creative Commons
Azamat Akhmetkaliyev,

Noura Alibrahim,

Darya Shafiee

и другие.

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Май 31, 2023

Epithelial mesenchymal transition (EMT) and epithelial (MET) are genetic determinants of cellular plasticity. These programs operate in physiological (embryonic development, wound healing) pathological (organ fibrosis, cancer) conditions. In cancer, EMT MET interfere with various signalling pathways at different levels. This results gross alterations the gene expression programs, which affect most, if not all hallmarks such as response to proliferative death-inducing signals, tumorigenicity, cell stemness. cancer cells involves large scale reorganisation cytoskeleton, loss integrity, gain traits, type migration. this regard, EMT/MET plasticity is highly relevant Go-or-Grow concept, postulates dichotomous relationship between motility proliferation. The decisions critically important processes takes central stage, mobilisation stem during healing, relapse, metastasis. Here we outline maintenance quiescence metastatic niches, focusing on implication regulatory networks switches. particular, discuss analogy residing hybrid quasi-mesenchymal states GAlert, an intermediate phase allowing quiescent enter cycle rapidly.

Язык: Английский

Процитировано

77
Landscape of epithelial–mesenchymal plasticity as an emergent property of coordinated teams in regulatory networks DOI Creative Commons
Kishore Hari,

Varun Ullanat,

Archana Balasubramanian

и другие.

eLife, Год журнала: 2022, Номер 11

Опубликована: Окт. 21, 2022

Elucidating the design principles of regulatory networks driving cellular decision-making has fundamental implications in mapping and eventually controlling cell-fate decisions. Despite being complex, these often only give rise to a few phenotypes. Previously, we identified two 'teams' nodes small cell lung cancer network that constrained phenotypic repertoire aligned strongly with dominant phenotypes obtained from simulations (Chauhan et al., 2021). However, it remained elusive whether exist other networks, how do they shape landscape. Here, demonstrate five different varying sizes governing epithelial-mesenchymal plasticity comprised players - one canonical drivers epithelial phenotype containing mesenchymal inducers. These are specific topology orchestrate bimodal landscape more frequent dynamically robust perturbations, relative intermediary/hybrid epithelial/mesenchymal ones. Our analysis reveals alone can contain information about corresponding distributions, thus obviating need simulate them. We propose as principle drive canalization diverse processes.

Язык: Английский

Процитировано

53
A role for partial epithelial-to-mesenchymal transition in enabling stemness in homeostasis and cancer DOI
Jeroen Verstappe, Geert Berx

Seminars in Cancer Biology, Год журнала: 2023, Номер 90, С. 15 - 28

Опубликована: Фев. 10, 2023

Язык: Английский

Процитировано

41
An integrative phenotype-structured partial differential equation model for the population dynamics of epithelial-mesenchymal transition DOI Creative Commons

Jules Guilberteau,

Paras Jain, Mohit Kumar Jolly

и другие.

npj Systems Biology and Applications, Год журнала: 2025, Номер 11(1)

Опубликована: Март 6, 2025

Phenotypic heterogeneity along the epithelial-mesenchymal (E-M) axis contributes to cancer metastasis and drug resistance. Recent experimental efforts have collated detailed time-course data on emergence dynamics of E-M in a cell population. However, it remains unclear how different intra- inter-cellular processes shape heterogeneity. Here, using Cell Population Balance model, we capture density phenotypic resulting from interplay between-(a) intracellular regulatory interaction among biomolecules, (b) division death (c) stochastic cell-state transition. We find that while existence depends regulation, gets enhanced with transitions diminished by growth rate differences. Further, resource competition cells can lead both bi-phasic total population and/or bi-stability composition. Overall, our model highlights complex between cellular shaping dynamic patterns

Язык: Английский

Процитировано

2
Unraveling non-genetic heterogeneity in cancer with dynamical models and computational tools DOI
Maalavika Pillai, Emilia Hojel, Mohit Kumar Jolly

и другие.

Nature Computational Science, Год журнала: 2023, Номер 3(4), С. 301 - 313

Опубликована: Апрель 24, 2023

Язык: Английский

Процитировано

23
Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state DOI Open Access
Paras Jain,

Sophia Corbo,

Kulsoom Mohammad

и другие.

Journal of The Royal Society Interface, Год журнала: 2023, Номер 20(198)

Опубликована: Янв. 1, 2023

Epithelial–mesenchymal transition (EMT) and its reverse mesenchymal–epithelial (MET) are critical during embryonic development, wound healing cancer metastasis. While phenotypic changes short-term EMT induction reversible, long-term has been often associated with irreversibility. Here, we show that seen in MCF10A cells upon by TGF β need not be irreversible, but have relatively longer time scales of reversibility than those induction. Next, using a phenomenological mathematical model to account for the chromatin-mediated epigenetic silencing miR-200 family ZEB family, highlight how memory gained can slow recovery epithelial state post-TGF withdrawal. Our results suggest modifiers govern extent scale advise caution against labelling as ‘irreversible’.

Язык: Английский

Процитировано

18
Augmenting Flexibility: Mutual Inhibition Between Inhibitory Neurons Expands Functional Diversity DOI Creative Commons
Belle Liu, Alexander James White, Chung‐Chuan Lo

и другие.

iScience, Год журнала: 2025, Номер 28(2), С. 111718 - 111718

Опубликована: Янв. 1, 2025

Recent advances in microcircuit analysis of nervous systems have revealed a plethora mutual connections between inhibitory interneurons across many different species and brain regions. The abundance these has not been fully explained. Strikingly, we show that neural circuits with mutually are able to rapidly flexibly switch distinct functions. That is, multiple functions coexist for single set synaptic weights. Here, develop theoretical framework explain how recurrent give rise this flexibility inhibition doubles the number cusp bifurcations small circuits. As concrete example, study class functional motifs call coupled excitatory loops (CRIRELs). These CRIRELs advantage being both multi-functional controllable, performing functions, including decisions, memory, toggle, so forth. Finally, demonstrate maximizes storage capacity larger networks.

Язык: Английский

Процитировано

1
Increased prevalence of hybrid epithelial/mesenchymal state and enhanced phenotypic heterogeneity in basal breast cancer DOI Creative Commons
Sarthak Sahoo,

Soundharya Ramu,

Madhumathy G Nair

и другие.

iScience, Год журнала: 2024, Номер 27(7), С. 110116 - 110116

Опубликована: Май 27, 2024

Highlights•Luminal signature is closely associated with epithelial in breast cancer•Basal correlates well a hybrid epithelial-mesenchymal signature•Basal cancer exhibits higher heterogeneity patterns•Mathematical modeling of underlying gene networks explains observed heterogeneitySummaryIntra-tumoral phenotypic promotes tumor relapse and therapeutic resistance remains an unsolved clinical challenge. Decoding the interconnections among different biological axes plasticity crucial to understand molecular origins heterogeneity. Here, we use multi-modal transcriptomic data—bulk, single-cell, spatial transcriptomics—from cell lines primary samples, identify associations between transition (EMT) luminal-basal plasticity—two key processes that enable We show luminal strongly associates state, but basal epithelial/mesenchymal phenotype(s) Mathematical core regulatory representative crosstalk elucidate mechanistic underpinnings from data. Our systems-based approach integrating data analysis mechanism-based offers predictive framework characterize intra-tumor interventions restrict it.Graphical abstract

Язык: Английский

Процитировано

6
Redox signalling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to p63 activation by HIF1α DOI Creative Commons
Zuen Ren, Malindrie Dharmaratne, Huizhi Liang

и другие.

British Journal of Cancer, Год журнала: 2024, Номер 130(6), С. 908 - 924

Опубликована: Янв. 18, 2024

Abstract Background Redox signaling caused by knockdown (KD) of Glutathione Peroxidase 2 (GPx2) in the PyMT mammary tumour model promotes metastasis via phenotypic and metabolic reprogramming. However, cell subpopulations transcriptional regulators governing these processes remained unknown. Methods We used single-cell transcriptomics to decipher stimulated GPx2 KD paired pulmonary metastases. analyzed EMT spectrum across various clusters using pseudotime trajectory analysis elucidated regulation hybrid state. Results Integration between PyMT/GPx2 primary lung metastases unraveled a basal/mesenchymal-like cluster several luminal-like spanning an spectrum. Interestingly, luminal at gained mesenchymal gene expression, resulting epithelial/mesenchymal fueled oxidative phosphorylation (OXPHOS) glycolysis. By contrast, distant metastasis, subpopulation OXPHOS, supporting adaptive plasticity. Furthermore, p63 was dramatically upregulated all clusters, implying role regulating partial MET sites, respectively. Importantly, effects were reversed HIF1α loss or gain function, suppression. Conclusions Collectively, results underscored dramatic effect redox on activation HIF1α, underlying plasticity leading metastasis.

Язык: Английский

Процитировано

5
Intersecting Pathways: The Role of Hybrid E/M Cells and Circulating Tumor Cells in Cancer Metastasis and Drug Resistance DOI
Amirali Hariri, Mina Mirian, Arezoo Khosravi

и другие.

Drug Resistance Updates, Год журнала: 2024, Номер 76, С. 101119 - 101119

Опубликована: Июль 14, 2024

Язык: Английский

Процитировано

5