Systems Biology of Cancer Metastasis

Cell Systems, Journal Year: 2019, Volume and Issue: 9(2), P. 109 - 127

Published: Aug. 1, 2019

Cancer metastasis is no longer viewed as a linear cascade of events but rather series concurrent, partially overlapping processes, successfully metastasizing cells assume new phenotypes while jettisoning older behaviors. The lack systemic understanding this complex phenomenon has limited progress in developing treatments for metastatic disease. Because traditionally been investigated distinct physiological compartments, the integration these and interlinked aspects remains challenge both systems-level experimental computational modeling metastasis. Here, we present some current perspectives on complexity cancer metastasis, multiscale nature its progression, view processes underlying invasive spread cells. We also highlight gaps our well insights emerging from interdisciplinary systems biology approaches to understand phenomenon.

Language: Английский

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Cellular Plasticity in Cancer

Cancer Discovery, Journal Year: 2019, Volume and Issue: 9(7), P. 837 - 851

Published: April 16, 2019

Abstract During cancer progression, tumor cells undergo molecular and phenotypic changes collectively referred to as cellular plasticity. Such result from microenvironmental cues, stochastic genetic epigenetic alterations, and/or treatment-imposed selective pressures, thereby contributing heterogeneity therapy resistance. Epithelial–mesenchymal plasticity is the best-known case of cell plasticity, but recent work has uncovered other examples, often with functional consequences. In this review, we explore nature role(s) these diverse programs in premalignant evolution, adaptation consider ways which targeting could lead novel anticancer treatments. Significance: Changes identity, or are common at different stages it become clear that can be a potent mediator progression chemoresistance. Understanding mechanisms underlying various forms may deliver new strategies for most lethal aspects cancer: metastasis resistance therapy.

Language: Английский

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EMT and MET: necessary or permissive for metastasis?

Molecular Oncology, Journal Year: 2017, Volume and Issue: 11(7), P. 755 - 769

Published: May 26, 2017

Epithelial‐to‐mesenchymal transition ( EMT ) and its reverse mesenchymal‐to‐epithelial MET have been suggested to play crucial roles in metastatic dissemination of carcinomas. These phenotypic transitions between states are not binary. Instead, carcinoma cells often exhibit a spectrum epithelial/mesenchymal phenotype(s). While plasticity has observed preclinically clinically, whether any these indispensable for outgrowth remains an unanswered question. Here, we focus on propose alternative mechanisms successful metastases beyond the traditional / view. We highlight multiple hypotheses that can help reconcile conflicting observations, outline next set key questions offer valuable insights into metastasis tumor models.

Language: Английский

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Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

Proceedings of the National Academy of Sciences, Journal Year: 2017, Volume and Issue: 114(12)

Published: March 7, 2017

Significance It is widely appreciated that carcinoma cells exhibiting certain mesenchymal traits are enriched for cancer stem (CSCs) and can give rise to tumors with aggressive features. Whereas it has been proposed cell populations internally heterogeneous, the field made little progress in resolving specific subtypes of pose greatest risk patients. We demonstrate utility integrin-β4 (ITGB4) segregating these into distinct subpopulations differing tumor-initiating abilities pathological behaviors. In addition, we identified mechanistic links between ZEB1 (zinc finger E-box binding homeobox 1) TAp63α (tumor protein 63 isoform as regulators ITGB4 expression be used a marker determine which patients more likely relapse after treatment.

Language: Английский

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Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas

Pharmacology & Therapeutics, Journal Year: 2018, Volume and Issue: 194, P. 161 - 184

Published: Sept. 27, 2018

Language: Английский

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EMT Factors and Metabolic Pathways in Cancer

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: April 7, 2020

The epithelial-mesenchymal transition (EMT) represents a biological program during which epithelial cells lose their cell identity and acquire mesenchymal phenotype. EMT is normally observed organismal development, wound healing tissue fibrosis. However, this process can be hijacked by cancer often associated with resistance to apoptosis, acquisition of invasiveness, stem characteristics treatment resistance. It becoming evident that complex, multifactorial spectrum, involving episodic, transient or partial events. Multiple factors have been causally implicated in including transcription (e.g., SNAIL, TWIST, ZEB), epigenetic modifications, microRNAs miR-200 family) more recently, long non-coding RNAs. the relevance metabolic pathways only recently being recognized. Importantly, alterations key affect development progression. In review, we report roles describe interactions interconnectedness. We introduce are involved EMT, glycolysis, TCA cycle, lipid amino acid metabolism, characterize relationship between metabolism. Finally, present therapeutic opportunities particular focus on pathways.

Language: Английский

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Distinct contributions of partial and full EMT to breast cancer malignancy

Developmental Cell, Journal Year: 2021, Volume and Issue: 56(23), P. 3203 - 3221.e11

Published: Nov. 29, 2021

Epithelial-mesenchymal transition (EMT) is a transient, reversible process of cell de-differentiation where cancer cells transit between various stages an EMT continuum, including epithelial, partial EMT, and mesenchymal states. We have employed Tamoxifen-inducible dual recombinase lineage tracing systems combined with live imaging 5-cell RNA sequencing to track undergoing or full in the MMTV-PyMT mouse model metastatic breast cancer. In primary tumors, infrequently undergo mostly epithelial states but rarely reach EMT. Cells contribute lung metastasis chemoresistance, whereas retain phenotype fail colonize lungs. However, are enriched recurrent tumors upon chemotherapy. Hence, continuum differentially hallmarks malignancy, such as tumor invasion, metastasis, chemoresistance.

Language: Английский

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Survival Outcomes in Cancer Patients Predicted by a Partial EMT Gene Expression Scoring Metric

Cancer Research, Journal Year: 2017, Volume and Issue: 77(22), P. 6415 - 6428

Published: Sept. 26, 2017

Abstract Metastasis is a significant contributor to morbidity and mortality for many cancer patients remains major obstacle effective treatment. In tissue types, metastasis fueled by the epithelial-to-mesenchymal transition (EMT)—a dynamic process characterized phenotypic morphologic changes concomitant with increased migratory invasive potential. Recent experimental theoretical evidence suggests that cells can be stably halted en route EMT in hybrid E/M phenotype. Cells this phenotype tend move collectively, forming clusters of circulating tumor are key tumor-initiating agents. Here, we developed an inferential model built on gene expression multiple subtypes devise metric characterizes degree which given cell line exhibits features. Our identified drivers fine-tuners epithelial–mesenchymal plasticity recapitulated behavior observed vitro experiments across types. We also predicted experimentally validated status certain lines, including DU145 A549. Finally, demonstrated relevance scores patient survival role characterizing aggressiveness subtype specific. algorithm promising tool quantify spectrum, investigate correlation score treatment response survival, provide important systematic clinical risk stratification Cancer Res; 77(22); 6415–28. ©2017 AACR.

Language: Английский

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Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States

Cells, Journal Year: 2018, Volume and Issue: 7(3), P. 21 - 21

Published: March 13, 2018

Aerobic glycolysis, also referred to as the Warburg effect, has been regarded dominant metabolic phenotype in cancer cells for a long time. More recently, it shown that mitochondria most tumors are not defective their ability carry out oxidative phosphorylation (OXPHOS). Instead, highly aggressive cells, mitochondrial energy pathways reprogrammed meet challenges of high demand, better utilization available fuels and macromolecular synthesis rapid cell division migration. Mitochondrial reprogramming is involved regulation oncogenic via mitochondria-to-nucleus retrograde signaling post-translational modification oncoproteins. In addition, neoplastic can engage crosstalk with tumor microenvironment. For example, signals from cancer-associated fibroblasts drive utilize OXPHOS, process known reverse effect. Emerging evidence shows acquire hybrid glycolysis/OXPHOS which both glycolysis OXPHOS be utilized production biomass synthesis. The facilitates plasticity may specifically associated metastasis therapy-resistance. Moreover, switch metabolism phenotypes response external stimuli survival. Taking into account heterogeneity therapies targeting dependency principle made more effective.

Language: Английский

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Epithelial–mesenchymal transition, a spectrum of states: Role in lung development, homeostasis, and disease

Developmental Dynamics, Journal Year: 2017, Volume and Issue: 247(3), P. 346 - 358

Published: June 24, 2017

Epithelial-mesenchymal transition (EMT) plays key roles during lung development and many diseases such as chronic obstructive pulmonary disease (COPD), cancer, fibrosis. Here, integrating morphological observations with underlying molecular mechanisms, we highlight the functional role of EMT in injury repair, discuss how it can contribute to pathogenesis disease. We evidence manifestation its potential driving COPD, idiopathic fibrosis (IPF), bronchiolitis obliterans syndrome (BOS), while noting that all cells need not display a full any these contexts, i.e., often co-express epithelial mesenchymal markers but do fully convert extracellular matrix (ECM) -producing fibroblasts. Finally, recent therapeutic attempts restrict Developmental Dynamics 247:346-358, 2018. © 2017 Wiley Periodicals, Inc.

Language: Английский

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